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Berraondo P, Cuesta R, Aranda F, Martinez-Riaño A, Eguren-Santamaria I, Luri-Rey C, Risson A, Melero A, Gomis G, Melero I. Immunocytokines and cytokine neutralization for cancer immunotherapy. Trends Cancer 2025:S2405-8033(25)00110-4. [PMID: 40425444 DOI: 10.1016/j.trecan.2025.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/09/2025] [Accepted: 04/22/2025] [Indexed: 05/29/2025]
Abstract
Despite deep and growing knowledge of cytokine functions, immunotherapies based on the control of these molecules have minimally impacted cancer patient management because of limited efficacy and narrow therapeutic windows. Opportunities to enhance efficacy and mitigate side effects arise from local delivery and targeting antitumor cytokines to tumor tissue via chimeric fusion with antibodies (immunocytokines). Conversely, neutralization of protumor cytokines using antibodies, cytokine traps, or receptor antagonists offer the opportunity to increase the efficacy of conventional immunotherapy with checkpoint inhibitors while reducing their side effects. Exploiting the immunobiology of interleukin (IL)-2, IL-12, IL-15, IL-18, and IL-21 in synergistic combinations with other treatments holds promise. The antagonistic neutralization of transforming growth factor-β, tumor necrosis factor, IL-1, IL-6, and CXCR1/2 chemokines and growth differentiation factor 15 also seems to be very convenient, again as part of combination strategies.
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Affiliation(s)
- Pedro Berraondo
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Raquel Cuesta
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Fernando Aranda
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Ana Martinez-Riaño
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Iñaki Eguren-Santamaria
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Department of Oncology, Clinica Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Carlos Luri-Rey
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Aline Risson
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Ana Melero
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Gabriel Gomis
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Department of Oncology, Clinica Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Nuffield Department of Medicine (NDM), University of Oxford, Oxford, UK.
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Spadotto V, Ripamonti C, Ghiroldi A, Galbiati E, Pozzi P, Noberini R, Bonaldi T, Steinkühler C, Fossati G. HDAC6 inhibition by ITF3756 modulates PD-L1 expression and monocyte phenotype: insights for a promising immune checkpoint blockade co-treatment therapy. Front Immunol 2025; 16:1546939. [PMID: 40433358 PMCID: PMC12106391 DOI: 10.3389/fimmu.2025.1546939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 04/15/2025] [Indexed: 05/29/2025] Open
Abstract
Introduction Tumor immunotherapy has revolutionized cancer treatment, particularly through the use of immune checkpoint inhibitors targeting the PD-L1/PD-1 axis. While PD-L1 expression on tumor cells is an established predictive biomarker for therapeutic response, emerging evidence highlights the importance of PD-L1 expression on myeloid cells, both in the periphery and within the tumor microenvironment (TME). This study explores the immunomodulatory effects of the selective HDAC6 inhibitor ITF3756 on monocytes and dendritic cells (DCs). Methods Monocytes were stimulated with the pro-inflammatory cytokine TNF-α and treated with ITF3756. PD-L1 and CD40 expression levels were assessed by flow cytometry. Transcriptomic and proteomic analyses were performed to characterize changes in gene and protein expression profiles. T cell proliferation was evaluated in co-culture assays. Additionally, the impact of ITF3756 was assessed in an in vivo murine model of colon cancer. Results ITF3756 effectively downregulated PD-L1 expression in TNF-α-activated monocytes and enhanced their costimulatory capacity by increasing CD40 expression. Transcriptomic and proteomic analyses revealed that ITF3756 counteracted TNF-α pathway activation and downregulated multiple inhibitory immune checkpoint molecules, promoting a less immunosuppressive phenotype. In co-culture assays, ITF3756-treated monocytes and DCs significantly enhanced T cell proliferation. In vivo, ITF3756 treatment led to reduced tumor growth in a colon cancer model. Discussion These findings demonstrate that selective HDAC6 inhibition by ITF3756 modulates myeloid cell functionality by diminishing inhibitory signals and promoting T cell activation. Thus, ITF3756 represents a promising immunomodulatory agent that could enhance the efficacy of immune checkpoint blockade in cancer immunotherapy.
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Affiliation(s)
| | | | - Andrea Ghiroldi
- New Drug Incubator Department, Italfarmaco Group, Milan, Italy
| | | | - Pietro Pozzi
- Preclinical Drug Development Department, Italfarmaco Group, Milan, Italy
| | - Roberta Noberini
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Tiziana Bonaldi
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hematology-Oncology (DIPO), University of Milan, Milan, Italy
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3
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Preet R, Islam MA, Shim J, Rajendran G, Mitra A, Vishwakarma V, Kutz C, Choudhury S, Pathak H, Dai Q, Sun W, Madan R, Zhong C, Markiewicz MA, Zhang J. Gut commensal Bifidobacterium-derived extracellular vesicles modulate the therapeutic effects of anti-PD-1 in lung cancer. Nat Commun 2025; 16:3500. [PMID: 40221398 PMCID: PMC11993705 DOI: 10.1038/s41467-025-58553-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 03/24/2025] [Indexed: 04/14/2025] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Although immunotherapy such as anti-programmed death-1 and its ligand 1 (PD-1/L1) is a standard treatment for advanced non-small cell lung cancer (NSCLC), many patients do not derive benefit directly. Several studies have elucidated new strategies to improve the antitumor immune response through gut microbiota modulation. However, it remains largely debatable regarding how gut microbiota remotely affect lung cancer microenvironment and subsequently modulate immunotherapy response. Here we show that commensal Bifidobacterium-derived extracellular vesicles (Bif.BEVs) can modulate the therapeutic effect of anti-PD-1 therapy in NSCLC. These Bif.BEVs are up-taken by lung cancer cells predominantly via dynamin-dependent endocytosis and upregulate PD-L1 expression through TLR4-NF-κB pathway. They also efficiently penetrate murine intestinal and patient-derived lung cancer organoids. Oral gavage of these Bif.BEVs result in their accumulation in tumors in mice. Using a syngeneic mouse model, Bif.BEVs are found to synergize the anti-tumor effect of anti-PD-1 via modulation of key cytokines, immune response and oncogenic pathways, and increase in tumor-infiltrating CD8+ T cells. Our study therefore identifies a link between Bif.BEVs and the tumor microenvironment, providing an alternative mechanism to explain how gut microbiota can influence immunotherapy response, particularly in tumors located anatomically distant from the gut.
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Affiliation(s)
- Ranjan Preet
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Md Atiqul Islam
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Jiyoung Shim
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Ganeshkumar Rajendran
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Amrita Mitra
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Vikalp Vishwakarma
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Caleb Kutz
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Sonali Choudhury
- Department of Cancer Biology, University of Kansas Comprehensive Cancer Center, Kansas City, KS, 66160, USA
| | - Harsh Pathak
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Qun Dai
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Weijing Sun
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Rashna Madan
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Cuncong Zhong
- Department of Electrical Engineering and Computer Science, University of Kansas, Lawrence, KS, 66045, USA
| | - Mary A Markiewicz
- Department of Microbiology, Molecular Genetics & Immunology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Jun Zhang
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
- Department of Cancer Biology, University of Kansas Comprehensive Cancer Center, Kansas City, KS, 66160, USA.
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Shekari N, Shanehbandi D, Baghbani E, Safaei S, Masoumi J, Baradaran B, Jalali SA. VSIG-3/IGSF11 silencing in A2058 melanoma cells simultaneously suppresses melanoma progression and induces anti-tumoral cytokine profile in human T cells: In silico and in vitro study. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:3861-3880. [PMID: 39365310 DOI: 10.1007/s00210-024-03491-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 09/24/2024] [Indexed: 10/05/2024]
Abstract
VISTA is a newly discovered immune checkpoint whose functional mechanisms have become increasingly important to study due to its brilliant results in cancer immunotherapy. Despite VSIG-3/IGSF11 being identified as an inhibitory ligand for VISTA with potential as a target for cancer immunotherapy, very little is known of its functions. This study aimed to conduct a detailed analysis of VSIG-3/IGSF11 in melanoma, as well as to study the effects of its silencing on melanoma cell line progression and human T cell functions. Online databases were used to investigate VSIG-3/IGSF11 expression, its relationships, and prognostic value in melanoma. Then, the effects of VSIG-3/IGSF11 silencing on proliferation, migration, cell cycle arrest, and apoptosis in A2058 melanoma cells were assessed using MTT, colony formation, wound healing, cell cycle, and Annexin-V FITC/PI assays, respectively. Finally, A2058 cells transfected with VSIG-3/IGSF11 siRNA were co-cultured with human T cells, and the expression levels of T cell cytokines were evaluated using qRT-PCR. VSIG-3/IGSF11 expression was significantly increased in melanoma patients and cell lines; however, no correlation was found between VSIG-3/IGSF11 expression levels and clinicopathological characteristics, survival, or immune cell infiltration. Following VSIG-3/IGSF11 silencing in A2058 cells, viability, proliferation, and migration rates were decreased, while apoptosis was increased. T cells co-cultured with VSIG-3/IGSF11 siRNA-transfected A2058 cells exhibited increased expression levels of IFN-γ and IL-12 and decreased expression levels of IL-10, TGF-β, and TNF-α. The inhibitory effect of VSIG-3/IGSF11 silencing on A2058 melanoma cell progression, along with the alteration of T cell cytokines towards a pro-inflammatory phenotype, suggests that VSIG-3/IGSF11 is primarily involved in melanoma progression and modulating immune responses. Therefore, it may be a valuable target for immunotherapy in melanoma patients.
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Affiliation(s)
- Najibeh Shekari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Baghbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Masoumi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Seyed Amir Jalali
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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5
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Wirbel C, Durand S, Boivin F, Plaschka M, Benboubker V, Grimont M, Barbollat-Boutrand L, Tondeur G, Balme B, Harou O, Eberhardt A, Dalle S, Lopez J, Caramel J. ZEB1 transcription factor induces tumor cell PD-L1 expression in melanoma. Cancer Immunol Immunother 2025; 74:141. [PMID: 40056177 PMCID: PMC11890833 DOI: 10.1007/s00262-025-03978-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 02/11/2025] [Indexed: 03/10/2025]
Abstract
Tumor cells can evade antitumor immune response by expressing the PD-L1 ligand, leading to the inhibition of PD-1-expressing T lymphocytes. The mechanisms that regulate PD-L1 expression in cancer cells are imperfectly characterized. The transcription factor ZEB1, a major regulator of phenotype switching in melanoma cells, was shown to promote immune escape in melanoma by repressing T cell infiltration. Using inducible models of phenotype switching and ZEB1 gain/loss-of-function melanoma, we show that ZEB1 binds to the CD274 (PD-L1) promoter, directly enhancing PD-L1 mRNA transcription and its expression at the cell membrane. Furthermore, using single-cell spatial analyses on human primary melanoma samples, we demonstrate the correlation of ZEB1 and PD-L1 expression in tumor cells. Overall, these data identify ZEB1-mediated regulation of PD-L1 tumor expression as a mechanism that could contribute to immune escape in melanoma.
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Affiliation(s)
- Chloé Wirbel
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Cell Plasticity in Melanoma" Team, Lyon, France
| | - Simon Durand
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Cell Plasticity in Melanoma" Team, Lyon, France
| | - Félix Boivin
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Cell Plasticity in Melanoma" Team, Lyon, France
| | - Maud Plaschka
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Cell Plasticity in Melanoma" Team, Lyon, France
| | - Valentin Benboubker
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Cell Plasticity in Melanoma" Team, Lyon, France
| | - Maxime Grimont
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Cell Plasticity in Melanoma" Team, Lyon, France
| | - Laetitia Barbollat-Boutrand
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Cell Plasticity in Melanoma" Team, Lyon, France
| | - Garance Tondeur
- Dermatology Unit, Hospices Civils de Lyon, CH Lyon Sud, 165 Chemin du Grand Revoyet, 69495, Pierre Bénite Cedex, France
| | - Brigitte Balme
- Dermatology Unit, Hospices Civils de Lyon, CH Lyon Sud, 165 Chemin du Grand Revoyet, 69495, Pierre Bénite Cedex, France
| | - Olivier Harou
- Dermatology Unit, Hospices Civils de Lyon, CH Lyon Sud, 165 Chemin du Grand Revoyet, 69495, Pierre Bénite Cedex, France
| | - Anaïs Eberhardt
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Cell Plasticity in Melanoma" Team, Lyon, France
- Dermatology Unit, Hospices Civils de Lyon, CH Lyon Sud, 165 Chemin du Grand Revoyet, 69495, Pierre Bénite Cedex, France
| | - Stéphane Dalle
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Cell Plasticity in Melanoma" Team, Lyon, France
- Dermatology Unit, Hospices Civils de Lyon, CH Lyon Sud, 165 Chemin du Grand Revoyet, 69495, Pierre Bénite Cedex, France
| | - Jonathan Lopez
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Cell Plasticity in Melanoma" Team, Lyon, France
- Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France
- Biochemistry and Molecular Biology Unit, Hospices Civils de Lyon, CH Lyon Sud, 165 Chemin du Grand Revoyet, 69495, Pierre Bénite Cedex, France
| | - Julie Caramel
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Cell Plasticity in Melanoma" Team, Lyon, France.
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6
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Szóstak N, Budnik M, Tomela K, Handschuh L, Samelak-Czajka A, Pietrzak B, Schmidt M, Kaczmarek M, Galus Ł, Mackiewicz J, Mackiewicz A, Kozlowski P, Philips A. Exploring correlations between gut mycobiome and lymphocytes in melanoma patients undergoing anti-PD-1 therapy. Cancer Immunol Immunother 2025; 74:110. [PMID: 39998665 PMCID: PMC11861499 DOI: 10.1007/s00262-024-03918-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 12/02/2024] [Indexed: 02/27/2025]
Abstract
Research has shown that the microbiome can influence how the immune system responds to melanoma cells, affecting the course of the disease and the outcome of the therapy. Here, we used the metagenomic approach and flow cytometry analyses of blood cells to discover correlations between gut fungi of metastatic melanoma patients enrolled in anti-PD-1 therapy and lymphocytes in their blood.We analyzed the patterns of associations before the first administration of anti-PD-1 therapy (BT, n = 61) and in the third month of the therapy (T3, n = 37), allowing us to track changes during treatment. To understand the possible impact of gut fungi on the efficacy of anti-PD-1 therapy, we analyzed the associations in clinical beneficiaries (CB, n = 37) and non-beneficiaries (NB, n = 24), as well as responders (R, n = 28) and non-responders (NR, n = 33).Patients with LDH < 338 units/L, overall survival (OS) > 12, CB, as well as R, had lower levels of Shannon diversity (p = 0.02, p = 0.05, p = 0.05, and p = 0.03, respectively). We found that the correlation pattern between intestinal fungi and lymphocytes was specific to the type of response, positive or negative. When comparing CB and NB groups, correlations with opposite directions were detected for C. albicans, suggesting a response-specific immune reaction. For CB, M. restricta exhibited a set of correlations with different types of lymphocytes, with prevalent positive correlations, suggesting a robust immune response in the CB group. This result extends our former research, where M. restricta and C. albicans were associated with an increased risk of melanoma progression and a poorer response to anti-PD-1 treatment.
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Affiliation(s)
- Natalia Szóstak
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.
| | - Michał Budnik
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Katarzyna Tomela
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866, Poznan, Poland
| | - Luiza Handschuh
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Anna Samelak-Czajka
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Bernadeta Pietrzak
- Department of Food Biotechnology and Microbiology, Poznan University of Life Sciences, Poznan, Poland
| | - Marcin Schmidt
- Department of Food Biotechnology and Microbiology, Poznan University of Life Sciences, Poznan, Poland
| | - Mariusz Kaczmarek
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866, Poznan, Poland
| | - Łukasz Galus
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866, Poznan, Poland
- Department of Medical and Experimental Oncology, Institute of Oncology, Poznan University of Medical Sciences, Poznan, Poland
| | - Jacek Mackiewicz
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866, Poznan, Poland
- Department of Medical and Experimental Oncology, Institute of Oncology, Poznan University of Medical Sciences, Poznan, Poland
| | - Andrzej Mackiewicz
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866, Poznan, Poland
| | - Piotr Kozlowski
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Anna Philips
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
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7
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Zhang Y, Wang P. A promising advance using oncolytic adenovirus to locally block tumorigenic TNF signaling. Mol Ther 2025; 33:443. [PMID: 39855190 PMCID: PMC11853352 DOI: 10.1016/j.ymthe.2025.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/08/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Affiliation(s)
- Yalei Zhang
- Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China; Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Peng Wang
- Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
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8
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Kang X, Han Y, Wu M, Li Y, Qian P, Xu C, Zou Z, Dong J, Wei J. In situ blockade of TNF-TNFR2 axis via oncolytic adenovirus improves antitumor efficacy in solid tumors. Mol Ther 2025; 33:670-687. [PMID: 39690741 PMCID: PMC11853363 DOI: 10.1016/j.ymthe.2024.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 07/13/2024] [Accepted: 12/10/2024] [Indexed: 12/19/2024] Open
Abstract
Tumor necrosis factor (TNF) has been recognized as an immune activation factor in tumor immunotherapy. Our study demonstrated that TNF blockade markedly enhanced the antitumor efficacy of oncolytic adenovirus (AdV) therapy. To minimize systemic side effects, we engineered a recombinant oncolytic AdV encoding a TNF inhibitor (AdV-TNFi) to confine TNF blockade within the tumor microenvironment (TME). AdV-TNFi significantly improved therapeutic outcomes across various solid tumor models, including four murine and two golden hamster cancers. Immune cell profiling identified CD8+ T cells as the primary mediators of AdV-TNFi-induced antitumor effects, rather than CD4+ T or NK cells. Additionally, AdV-TNFi significantly decreased the infiltration of suppressive myeloid-derived immune cells within the TME and promoted long-term antitumor immune surveillance. Further investigation indicated that TNFR2, more than TNFR1, is pertinent to the immunosuppressive TME, with a recombinant AdV-encoding anti-TNFR2 demonstrating comparable antitumor efficacy to AdV-TNFi. Moreover, AdV-TNFi enhanced the antitumor efficacy of gemcitabine and immune checkpoint blockades (ICBs), such as anti-PD-L1 and anti-TIGIT antibodies, in pancreatic carcinoma and the anti-EGFR antibody in colon carcinoma. In conclusion, intratumoral blockade of the TNF/TNFR2 axis using AdV augments cancer immunotherapy efficacy while mitigating the risks associated with systemic TNF or TNFR2 suppression, warranting further clinical investigation.
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MESH Headings
- Humans
- Animals
- Cricetinae
- Cell Line
- Male
- Mice
- Mice, Inbred C57BL
- Adenoviridae/genetics
- Tumor Necrosis Factors/chemistry
- Tumor Necrosis Factors/genetics
- Tumor Necrosis Factors/metabolism
- Receptors, Tumor Necrosis Factor, Type II/chemistry
- Receptors, Tumor Necrosis Factor, Type II/genetics
- Receptors, Tumor Necrosis Factor, Type II/metabolism
- Neoplasms/genetics
- Neoplasms/metabolism
- Neoplasms/pathology
- Disease Progression
- Mice, Inbred BALB C
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Receptors, Tumor Necrosis Factor, Type I/metabolism
- Lymphocytes, Tumor-Infiltrating/immunology
- CD8-Positive T-Lymphocytes/immunology
- Protein Binding
- Models, Molecular
- Protein Structure, Tertiary
- Protein Structure, Quaternary
- Immune Checkpoint Inhibitors/pharmacology
- Tyrosine Kinase Inhibitors/pharmacology
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Affiliation(s)
- Xiaozhen Kang
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Yifeng Han
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Mengdi Wu
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Yuxin Li
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Peng Qian
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Chuning Xu
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Zhengyun Zou
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jie Dong
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China; Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China.
| | - Jiwu Wei
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China.
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9
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Joshkon A, Traboulsi W, Terme M, Bachelier R, Fayyad-Kazan H, Dignat-George F, Foucault-Bertaud A, Leroyer AS, Bardin N, Blot-Chabaud M. Soluble CD146 Cooperates with VEGFa to Generate an Immunosuppressive Microenvironment in CD146-Positive Tumors: Interest of a Combined Antibody-Based Therapy. Mol Cancer Ther 2025; 24:275-285. [PMID: 39431288 DOI: 10.1158/1535-7163.mct-24-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 07/09/2024] [Accepted: 10/17/2024] [Indexed: 10/22/2024]
Abstract
Tumor development necessitates immune escape through different mechanisms. To counteract these effects, the development of therapies targeting immune checkpoints (ICP) has generated interest as they have produced lasting objective responses in patients with advanced metastatic tumors. However, many tumors do not respond to inhibitors of ICPs, necessitating to further study the underlying mechanisms of exhaustion. VEGFa, a proangiogenic molecule secreted by tumors, was described to participate to tumor immune exhaustion by increasing ICPs, justifying in part the use of an anti-VEGFa mAb, bevacizumab, in patients. However, recent studies from our group have demonstrated that tumors can escape anti-VEGFa therapy through the secretion of soluble CD146 (sCD146). In this study, we show that both VEGFa and sCD146 cooperate to create an immunosuppressive microenvironment by increasing the expression of ICPs. In addition, sCD146 favors protumoral M2-type macrophages and induces the secretion of proinflammatory cytokines. An anti-sCD146 mAb reverses these effects and displays additive effects with the anti-VEGFa antibody to eliminate tumors in a syngeneic murine model grafted with melanoma cells. Combining bevacizumab with mucizumab could thus be of major therapeutic interest to prevent immune escape in malignant melanoma and other CD146-positive tumors.
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Affiliation(s)
- Ahmad Joshkon
- Aix-Marseille Univ, INSERM1263, INRAE1260, C2VN, Marseille, France
- Massalia Therapeutics, Marseille, France
| | - Wael Traboulsi
- Aix-Marseille Univ, INSERM1263, INRAE1260, C2VN, Marseille, France
| | - Magali Terme
- Université Paris Cité, Inserm, PARCC, Paris, France
| | | | - Hussein Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Science, Lebanese University, Hadath, Lebanon
| | | | | | | | - Nathalie Bardin
- Aix-Marseille Univ, INSERM1263, INRAE1260, C2VN, Marseille, France
- Massalia Therapeutics, Marseille, France
- Laboratory of Immunology, Biogenopole, APHM, Marseille, France
| | - Marcel Blot-Chabaud
- Aix-Marseille Univ, INSERM1263, INRAE1260, C2VN, Marseille, France
- Massalia Therapeutics, Marseille, France
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10
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Cho NW, Guldberg SM, Nabet BY, Yu JZ, Kim EJ, Hiam-Galvez KJ, Yee JL, DeBarge R, Tenvooren I, Ashitey NA, Lynce F, Dillon DA, Rosenbluth JM, Spitzer MH. T Cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL1 and TNFα Inflammation. Cancer Immunol Res 2025; 13:229-244. [PMID: 39404741 PMCID: PMC11790381 DOI: 10.1158/2326-6066.cir-24-0416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 07/10/2024] [Accepted: 10/11/2024] [Indexed: 02/04/2025]
Abstract
Resistance to immune checkpoint inhibitors (ICI) is common, even in tumors with T-cell infiltration. We thus investigated consequences of ICI-induced T-cell infiltration in the microenvironment of resistant tumors. T cells and neutrophil numbers increased in ICI-resistant tumors following treatment, in contrast to ICI-responsive tumors. Resistant tumors were distinguished by high expression of IL1 receptor 1, enabling a synergistic response to IL1 and TNFα to induce G-CSF, CXCL1, and CXCL2 via NF-κB signaling, supporting immunosuppressive neutrophil accumulation in tumor. Perturbation of this inflammatory resistance circuit sensitized tumors to ICIs. Paradoxically, T cells drove this resistance circuit via TNFα both in vitro and in vivo. Evidence of this inflammatory resistance circuit and its impact also translated to human cancers. These data support a mechanism of ICI resistance, wherein treatment-induced T-cell activity can drive resistance in tumors responsive to IL1 and TNFα, with important therapeutic implications.
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Affiliation(s)
- Nam Woo Cho
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
- Departments of Otolaryngology and Microbiology & Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA
| | - Sophia M. Guldberg
- Departments of Otolaryngology and Microbiology & Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA
- Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Barzin Y. Nabet
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA *present address: Genentech Inc., South San Francisco, CA, USA
| | - Jie Zeng Yu
- Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA
| | | | - Kamir J. Hiam-Galvez
- Departments of Otolaryngology and Microbiology & Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA
- Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Jacqueline L. Yee
- Departments of Otolaryngology and Microbiology & Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA
- Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Rachel DeBarge
- Departments of Otolaryngology and Microbiology & Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA
- Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Iliana Tenvooren
- Departments of Otolaryngology and Microbiology & Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA
| | - Naa Asheley Ashitey
- Departments of Otolaryngology and Microbiology & Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA
| | | | - Deborah A. Dillon
- Department of Pathology, Brigham & Women’s Hospital, Boston, MA, USA
| | - Jennifer M. Rosenbluth
- Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, and Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - Matthew H. Spitzer
- Departments of Otolaryngology and Microbiology & Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA
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11
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Efentakis P, Choustoulaki A, Kwiatkowski G, Varela A, Kostopoulos IV, Tsekenis G, Ntanasis-Stathopoulos I, Georgoulis A, Vorgias CE, Gakiopoulou H, Briasoulis A, Davos CH, Kostomitsopoulos N, Tsitsilonis O, Dimopoulos MA, Terpos E, Chłopicki S, Gavriatopoulou M, Andreadou I. Early microvascular coronary endothelial dysfunction precedes pembrolizumab-induced cardiotoxicity. Preventive role of high dose of atorvastatin. Basic Res Cardiol 2025; 120:263-286. [PMID: 38520533 PMCID: PMC11790778 DOI: 10.1007/s00395-024-01046-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/07/2024] [Accepted: 03/08/2024] [Indexed: 03/25/2024]
Abstract
Immune checkpoint inhibitors (ICIs) exhibit remarkable antitumor activity and immune-related cardiotoxicity of unknown pathomechanism. The aim of the study was to investigate the ICI class-dependent cardiotoxicity in vitro and pembrolizumab's (Pem's) cardiotoxicity in vivo, seeking for translational prevention means. Cytotoxicity was investigated in primary cardiomyocytes and splenocytes, incubated with ipilimumab, Pem and avelumab. Pem's cross-reactivity was assessed by circular dichroism (CD) on biotechnologically produced human and murine PD-1 and in silico. C57BL6/J male mice received IgG4 or Pem for 2 and 5 weeks. Echocardiography, histology, and molecular analyses were performed. Coronary blood flow velocity mapping and cardiac magnetic resonance imaging were conducted at 2 weeks. Human EA.hy926 endothelial cells were incubated with Pem-conditioned media from human mononuclear cells, in presence and absence of statins and viability and molecular signaling were assessed. Atorvastatin (20 mg/kg, daily) was administered in vivo, as prophylaxis. Only Pem exerted immune-related cytotoxicity in vitro. Pem's cross-reactivity with the murine PD-1 was confirmed by CD and docking. In vivo, Pem initiated coronary endothelial and diastolic dysfunction at 2 weeks and systolic dysfunction at 5 weeks. At 2 weeks, Pem induced ICAM-1 and iNOS expression and intracardiac leukocyte infiltration. At 5 weeks, Pem exacerbated endothelial activation and triggered cardiac inflammation. Pem led to immune-related cytotoxicity in EA.hy926 cells, which was prevented by atorvastatin. Atorvastatin mitigated functional deficits, by inhibiting endothelial dysfunction in vivo. We established for the first time an in vivo model of Pem-induced cardiotoxicity. Coronary endothelial dysfunction precedes Pem-induced cardiotoxicity, whereas atorvastatin emerges as a novel prophylactic therapy.
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MESH Headings
- Animals
- Atorvastatin/administration & dosage
- Atorvastatin/pharmacology
- Mice, Inbred C57BL
- Humans
- Male
- Cardiotoxicity/prevention & control
- Antibodies, Monoclonal, Humanized/toxicity
- Mice
- Immune Checkpoint Inhibitors/toxicity
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/physiopathology
- Endothelium, Vascular/metabolism
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Coronary Vessels/drug effects
- Coronary Vessels/physiopathology
- Coronary Vessels/metabolism
- Disease Models, Animal
- Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Antineoplastic Agents, Immunological/toxicity
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Affiliation(s)
- Panagiotis Efentakis
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, 15771, Athens, Greece
| | - Angeliki Choustoulaki
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, 15771, Athens, Greece
| | - Grzegorz Kwiatkowski
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland
| | - Aimilia Varela
- Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Ioannis V Kostopoulos
- Flow Cytometry Unit, Section of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - George Tsekenis
- Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasios Georgoulis
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, 15771, Athens, Greece
| | - Constantinos E Vorgias
- Department of Biochemistry & Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Harikleia Gakiopoulou
- Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexandros Briasoulis
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | - Ourania Tsitsilonis
- Flow Cytometry Unit, Section of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Evangelos Terpos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Stefan Chłopicki
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland
- Medical College, Jagiellonian University, Krakow, Poland
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, 15771, Athens, Greece.
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12
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Kang L, Cao J, Guo W, Cui X, Wei Y, Zhang J, Liu F, Duan C, Lin Q, Lv P, Ni Z, Zuo J, Shen H. Tumor Necrosis Factor-α-Dependent Inflammation Upregulates High Mobility Group Box 1 To Induce Tumor Promotion and Anti-Programmed Cell Death Protein-1 Immunotherapy Resistance in Lung Adenocarcinoma. J Transl Med 2025; 105:102164. [PMID: 39461427 DOI: 10.1016/j.labinv.2024.102164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 09/17/2024] [Accepted: 10/18/2024] [Indexed: 10/29/2024] Open
Abstract
Tumor-associated chronic lung inflammation depends on tumor necrosis factor (TNF)-α to activate several cytokines as part of an inflammatory loop, which plays a critical role in tumor progression in lung adenocarcinoma. High mobility group box 1 (HMGB1) is a cytokine that mediates inflammation. Whether TNF-α-induced inflammation regulates HMGB1 to contribute to tumor progression and promotion in lung adenocarcinoma remains unclear. Thus, human samples and a urethane-induced inflammation-driven lung adenocarcinoma (IDLA) mouse model were used to explore the involvement of HMGB1 in tumorigenesis and tumor progression and efficacy of anti-programmed cell death protein (PD)-1 immunotherapy. High levels of HMGB1 were observed in human lung adenocarcinoma associated with poor overall survival in patients. HMGB1 upregulation was positively correlated with TNF-α-related inflammation and TIM-3+ infiltration. TNF-α upregulated intracellular and extracellular HMGB1 expression to contribute to tumor promotion in A549 cells in vitro. Using a urethane-induced IDLA mouse model, we found HMGB1 upregulation was associated with increased TIM-3+ T-cell infiltration. Blocking TNF-α-dependent inflammation downregulated HMGB1 expression and inhibited tumorigenesis in the IDLA model. Anti-PD-1 treatment alone did not inhibit tumor growth in the TNF-α-dependent IDLA, whereas anti-PD-1 combined with TNF-α blockade overcame anti-PD-1 immunotherapy resistance. Furthermore, anti-PD-1 combined with anti-HMGB1 also inhibited tumor growth in IDLA, suggesting that increased HMGB1 release by TNF-α contributes to the resistance of anti-PD-1 immunotherapy in IDLA. Thus, tumor-associated TNF-α-dependent inflammation upregulated intracellular and extracellular HMGB1 expression in an inflammatory loop, contributing to tumor promotion and anti-PD-1 immunotherapy resistance in lung adenocarcinoma.
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Affiliation(s)
- Lifei Kang
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China; Department of Pathology, Hebei Chest Hospital, Shijiazhuang, China
| | - Jingjing Cao
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China; Center of Metabolic Diseases and Cancer Research, Hebei Medical University, Shijiazhuang, China; Department of Pathology, Lishui Central Hospital of Zhejiang Province, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Wenli Guo
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China; Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China
| | - Xiaohui Cui
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China; Center of Metabolic Diseases and Cancer Research, Hebei Medical University, Shijiazhuang, China
| | - Yangxuan Wei
- Center of Metabolic Diseases and Cancer Research, Hebei Medical University, Shijiazhuang, China
| | - Jiayu Zhang
- Center of Metabolic Diseases and Cancer Research, Hebei Medical University, Shijiazhuang, China
| | - Feiran Liu
- Department of Oncology, The Fourth Hospital, Hebei Medical University, Shijiazhuang, China
| | - Chenyang Duan
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China; Center of Metabolic Diseases and Cancer Research, Hebei Medical University, Shijiazhuang, China
| | - Qiang Lin
- Department of Oncology, North China Petroleum Bureau General Hospital of Hebei Medical University, Renqiu, China
| | - Ping Lv
- Department of Pharmacology, Hebei Medical University, Shijiazhuang, China
| | - Zhiyu Ni
- Affiliated Hospital of Hebei University of Engineering, Handan, China; Clinical Medical College, Hebei University of Engineering, Handan, China; Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding, China.
| | - Jing Zuo
- Center of Metabolic Diseases and Cancer Research, Hebei Medical University, Shijiazhuang, China; Department of Oncology, The Fourth Hospital, Hebei Medical University, Shijiazhuang, China; Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding, China.
| | - Haitao Shen
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China; Center of Metabolic Diseases and Cancer Research, Hebei Medical University, Shijiazhuang, China; Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding, China.
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13
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Zhao Z, Fetse J, Mamani UF, Guo Y, Li Y, Patel P, Liu Y, Lin CY, Li Y, Mustafa B, Cheng K. Development of a peptide-based tumor-activated checkpoint inhibitor for cancer immunotherapy. Acta Biomater 2025; 193:484-497. [PMID: 39716541 PMCID: PMC11788053 DOI: 10.1016/j.actbio.2024.12.051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 12/13/2024] [Accepted: 12/19/2024] [Indexed: 12/25/2024]
Abstract
Antibody-based checkpoint inhibitors have achieved great success in cancer immunotherapy, but their uncontrollable immune-related adverse events remain a major challenge. In this study, we developed a tumor-activated nanoparticle that is specifically active in tumors but not in normal tissues. We discovered a short anti-PD-L1 peptide that blocks the PD-1/PD-L1 interaction. The peptide was modified with a PEG chain through a novel matrix metalloproteinase-2 (MMP-2)-specific cleavage linker. The modified TR3 peptide self-assembles into a micelle-like nanoparticle (TR3-M-NP), which remains inactive and unable to block the PD-1/PD-L1 interaction in its native form. However, upon cleavage by MMP-2 in tumors, it releases the active peptide. The TR3-M-NP5k nanoparticle was specifically activated in tumors through enzyme-mediated cleavage, leading to the inhibition of tumor growth and extended survival compared to control groups. In summary, TR3-M-NP shows great potential as a tumor-responsive immunotherapy agent with reduced toxicities. STATEMENT OF SIGNIFICANCE: In this study, we developed a bioactive peptide-based checkpoint inhibitor that is active only in tumors and not in normal tissues, thereby potentially avoiding immune-related adverse effects. We discovered a short anti-PD-L1 peptide, TR3, that blocks the PD-1/PD-L1 interaction. We chemically modified the TR3 peptide to self-assemble into a micelle-like nanoparticle (TR3-M-NP), which itself cannot block the PD-1/PD-L1 interaction but releases the active TR3 peptide in tumors upon cleavage by MMP-2. In contrast, the nanoparticle is randomly degraded in normal tissues into peptides fragments that cannot block the PD-1/PD-L1 interaction. Upon intraperitoneal injection, TR3-M-NP5k was activated specifically in tumors through enzyme cleavage, leading to the inhibition of tumor growth and extended survival compared to the control groups. In summary, TR3-M-NP holds significant promise as a tumor-responsive immunotherapy agent with reduced toxicities. The bioactive platform has the potential to be used for other types of checkpoint inhibitor.
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Affiliation(s)
- Zhen Zhao
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - John Fetse
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Umar-Farouk Mamani
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Yuhan Guo
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Yuanke Li
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Pratikkumar Patel
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Yanli Liu
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Chien-Yu Lin
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Yongren Li
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Bahaa Mustafa
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
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14
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Ben-Baruch A. The Tumor Immune Environment: Advances in the Cancer Immunotherapy Era. Methods Mol Biol 2025; 2926:15-34. [PMID: 40266514 DOI: 10.1007/978-1-0716-4542-0_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
For over the last hundred years, the scientific community has demonstrated much interest in the roles of the immune system in regulating tumor progression. Extensive research that was performed in this context has revealed that mechanisms of acquired immunity can be highly potent in eradicating cancer cells, if given the right conditions to do so. Basic and clinical studies have paved the way toward the design of sophisticated modalities that improve the ability of T cells to efficiently recognize cancer antigens (when expressed by the tumor cells) and to expand thereafter; alongside developing procedures that prevent immune suppression caused by inhibitory immune checkpoints, these approaches offer cancer patients improved immunotherapies, which increase remission and prolong survival. The current chapter provides a summary of key aspects relevant to such immunotherapies, including the following: (1) cancer vaccines that enhance cancer antigen presentation; (2) adoptive cell transfer (ACT)-based therapies, like tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor expressing T cells (CAR-T cells); and (3) immune checkpoint blockades (ICBs) that downregulate the extent of immune suppression mediated by inhibitory immune checkpoint molecules, like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligands, primarily PD-L1 (and also PD-L2). These treatments have revolutionized the immunotherapy field, demonstrating the strong power of acquired immunity in preventing tumor growth and progression, giving much hope to cancer patients worldwide.
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Affiliation(s)
- Adit Ben-Baruch
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
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15
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Mao R, Liu S, Dolan JC, Schmidt BL, Tao F. Programmed Cell Death Protein 1 Contributes to Oral Cancer Pain via Regulating Tumor Necrosis Factor Alpha in the Spinal Trigeminal Nucleus Caudalis. Curr Neuropharmacol 2025; 23:594-601. [PMID: 39660489 PMCID: PMC12163463 DOI: 10.2174/1570159x23666241209160039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/08/2024] [Accepted: 05/19/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Oral cancer causes intense pain at the primary site, and such pain can impair oral functions. However, the underlying mechanisms for oral cancer pain are still not fully understood. In the present study, it is investigated whether programmed cell death protein 1 (PD-1) is involved in the development of oral cancer pain. METHODS RMP1-14, a specific anti-PD-1 antibody, was injected into spinal trigeminal nucleus caudalis (Sp5C) and measured pain behaviors using von Frey filaments and dolognawmeter. Western blotting and immunofluorescence staining were performed to analyze the expression of PD-1 and tumor necrosis factor alpha (TNFα) in the Sp5C. RESULTS It was observed that the PD-1 antibody significantly inhibited mechanical hypersensitivity and functional allodynia in our oral cancer pain mouse model. Moreover, we found that TNFα was highly upregulated in the Sp5C following the induction of oral cancer pain and that intra-Sp5C injection of the PD-1 antibody diminished the upregulation of TNFα. It was found that genetic deletion of TNFα or its receptor antagonism synergized the analgesic effect of PD-1 antibody on oral cancer pain. CONCLUSION Our results suggest that PD-1 in the Sp5C contributes to oral cancer pain by altering TNFα signaling in the trigeminal nociceptive system, and PD-1 could be targeted to develop a novel approach for oral cancer pain management.
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Affiliation(s)
- Runyi Mao
- Department of Biomedical Sciences, Texas A&M University School of Dentistry, Dallas, Texas, USA
| | - Sufang Liu
- Department of Biomedical Sciences, Texas A&M University School of Dentistry, Dallas, Texas, USA
| | - John C. Dolan
- NYU Dentistry Translational Research Center, New York University College of Dentistry, New York, NY, USA
| | - Brian L. Schmidt
- NYU Dentistry Translational Research Center, New York University College of Dentistry, New York, NY, USA
- Pain Research Center, New York University, New York, NY, USA
| | - Feng Tao
- Department of Biomedical Sciences, Texas A&M University School of Dentistry, Dallas, Texas, USA
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16
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Strouse J, Chan KK, Baccile R, He G, Louden DKN, Giurcanu M, Singh A, Rieth J, Abdel-Wahab N, Katsumoto TR, Singh N, Rouhani S, Reid P. Impact of steroid-sparing immunosuppressive agents on tumor outcome in the context of cancer immunotherapy with highlight on melanoma: a systematic literature review and meta-analysis. Front Immunol 2024; 15:1499478. [PMID: 39737191 PMCID: PMC11682972 DOI: 10.3389/fimmu.2024.1499478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 11/25/2024] [Indexed: 01/01/2025] Open
Abstract
Background The impact of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on tumor outcome is not well-known. This systematic review evaluates tumor outcomes for corticosteroid (CS) monotherapy versus CS with SSIA (CS-SSIA) for irAE treatment with a focus on melanoma. Methods Search was conducted through 1/5/23 using PubMed, Embase, Cochrane CENTRAL, and Web of Science. We included case series, retrospective/prospective observational studies and interventional clinical trials. Individual-level data was analyzed using KM curves and Cox regression for overall survival (OS) and progression free survival (PFS). Time to SSIA was treated as a time-varying exposure using landmark analysis (landmark timepoint=3 months after irAE) to account for immortal time bias. For group-level data, meta-analysis compared the use of SSIA to No SSIA for irAEs. Results Of twenty-two publications with individual-level data, 147 patients with any cancer (57 CS, 90 CS-SSIA) and 65 with melanoma (18 CS, 47 CS-SSIA) underwent landmark analysis. Twenty-two publications underwent group-level evaluation and four were included in the meta-analysis. CS-SSIA versus CS showed higher risk of all-cause mortality and progression (HR 2.75, 95%CI: 1.44-5.27, p<0.01 and HR 1.75, 95%CI: 1.07-2.85, p=0.03, respectively). Melanoma showed worse OS and PFS for CS-SSIA versus CS (HR 5.68, 95%CI: 1.31-24.67, p=0.02 and HR 2.68, 95%CI: 1.12-6.40, p=0.03, respectively). In the meta-analysis of group-level data (n=2558), we found worse OS and PFS for CS-SSIA versus No SSIA (HR 1.58, 95%CI: 1.25; 2.01, p<0.01 and 1.70, 95%CI: 1.25-2.33, p<0.01). Tumor necrosis factor-alpha inhibitors (TNFi) were the most common SSIA. In the melanoma cohort, TNFi had worse OS and PFS versus CS (HR 6.46, 95%CI: 1.43-29.19, p = 0.02 and HR 7.49, 95%CI: 2.29-24.48, p<0.01, respectively). TNFi versus Other SSIAs showed a trend toward worse OS and worse PFS (HR 6.96, 95%CI: 0.90-53.65, p=0.06 and HR 21.5, 95%CI: 2.63-175.8, p<0.01, respectively). Meta-analysis showed a concern for TNFi compared to Other SSIA (HR 1.56, 95%CI: 1.17-2.09, p<0.01 respectively). Conclusions While our results raise concern about the effects of CS-SSIA and TNFi for irAE therapy on tumor outcomes, prospective randomized controlled trials are needed to definitively assess the effect of SSIAs on tumor outcomes.
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Affiliation(s)
- Jennifer Strouse
- Division of Immunology, University of Iowa, Iowa City, IA, United States
| | - Karmela Kimi Chan
- Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, NY, United States
| | - Rachel Baccile
- Center for Health and The Social Sciences, University of Chicago, Chicago, IL, United States
| | - Gong He
- Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, United States
| | - Diana K. N. Louden
- University Libraries, University of Washington, Seattle, WA, United States
| | - Mihai Giurcanu
- Department of Public Health Sciences, University of Chicago, Chicago, IL, United States
| | - Arohi Singh
- University of Chicago Medicine, Chicago, IL, United States
| | - John Rieth
- Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Iowa Health Care, Iowa City, IA, United States
| | - Noha Abdel-Wahab
- Section of Rheumatology & Clinical Immunology, Department of General Internal Medicine, and Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Rheumatology & Rehabilitation, Assiut University Hospitals, Assiut University Faculty of Medicine, Asyut, Egypt
| | - Tamiko R. Katsumoto
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, United States
| | - Namrata Singh
- Division of Rheumatology, University of Washington, Seattle, WA, United States
| | - Sherin Rouhani
- Mass General Cancer Center, Massachusetts General Hospital, Boston, MA, United States
| | - Pankti Reid
- Division of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, United States
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17
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Javed SR, Skolariki A, Zameer MZ, Lord SR. Implications of obesity and insulin resistance for the treatment of oestrogen receptor-positive breast cancer. Br J Cancer 2024; 131:1724-1736. [PMID: 39251829 PMCID: PMC11589622 DOI: 10.1038/s41416-024-02833-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 08/13/2024] [Accepted: 08/19/2024] [Indexed: 09/11/2024] Open
Abstract
Breast cancer is the most common cancer in women, and incidence rates are rising, it is thought in part, due to increasing levels of obesity. Endocrine therapy (ET) remains the cornerstone of systemic therapy for early and advanced oestrogen receptor-positive (ER + ) breast cancer, but despite treatment advances, it is becoming more evident that obesity and insulin resistance are associated with worse outcomes. Here, we describe the current understanding of the relationship between both obesity and diabetes and the prevalence and outcomes for ER+ breast cancer. We also discuss the mechanisms associated with resistance to ET and the relationship to treatment toxicity.
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Affiliation(s)
| | | | | | - Simon R Lord
- Department of Oncology, University of Oxford, Oxford, UK.
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18
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Penna F, Rubini G, Costelli P. Immunomodulation: A new approach to cancer cachexia, potentially suitable for aging. Mol Aspects Med 2024; 100:101318. [PMID: 39260232 DOI: 10.1016/j.mam.2024.101318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 07/18/2024] [Accepted: 09/05/2024] [Indexed: 09/13/2024]
Abstract
Cancer cachexia is the prototypical example of comorbidity, occurring in most of cancer patients. It is a direct consequence of tumor growth and of the associated inflammatory/immune response. Cachexia can be exacerbated by anti-cancer therapies, frequently resulting in dose limitation and/or treatment delay or discontinuation. The pathogenesis of cancer cachexia is still unclear and includes nutritional, metabolic, hormonal and immunological components. Tumor ability to shape the immune response to its own advantage is now well accepted, while the possibility that such an altered immune response could play a role in the onset of cachexia is still an undefined issue. Indeed, most of the immune-related research on cachexia mainly focused on pro-inflammatory mediators, almost totally disregarding the interactions among immune cells and the homeostasis of peripheral tissues. The present review provides an overview of the immune system dysregulations occurring in cancer cachexia, focusing on the possibility that immunomodulating strategies, mainly developed to stimulate the anti-cancer immune response, could be useful to counteract cachexia as well. Cancer and cachexia are frequent comorbidities of aging. Along this line, cancer- and aging-associated muscle wasting likely coexist in the same patients. Since both conditions share some of the underlying mechanisms, the potential effectiveness of immunomodulation on sarcopenia of aging is discussed.
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Affiliation(s)
- Fabio Penna
- Department of Clinical and Biological Sciences, University of Turin, Italy
| | - Giacomo Rubini
- Department of Clinical and Biological Sciences, University of Turin, Italy
| | - Paola Costelli
- Department of Clinical and Biological Sciences, University of Turin, Italy.
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19
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McCulloch TR, Rossi GR, Alim L, Lam PY, Wong JKM, Coleborn E, Kumari S, Keane C, Kueh AJ, Herold MJ, Wilhelm C, Knolle PA, Kane L, Wells TJ, Souza-Fonseca-Guimaraes F. Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation. Nat Commun 2024; 15:9871. [PMID: 39543125 PMCID: PMC11564688 DOI: 10.1038/s41467-024-54232-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 11/05/2024] [Indexed: 11/17/2024] Open
Abstract
Natural killer (NK) cell function is regulated by a balance of activating and inhibitory signals. Tumor necrosis factor (TNF) is an inflammatory cytokine ubiquitous across homeostasis and disease, yet its role in regulation of NK cells remains unclear. Here, we find upregulation of the immune checkpoint protein, T cell immunoglobulin and mucin domain 3 (Tim3), is a biomarker of TNF signaling in NK cells during Salmonella Typhimurium infection. In mice with conditional deficiency of either TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2) in NK cells, we find TNFR1 limits bacterial clearance whereas TNFR2 promotes it. Mechanistically, via single cell RNA sequencing we find that both TNFR1 and TNFR2 induce the upregulation of Tim3, while TNFR1 accelerates NK cell death but TNFR2 promotes NK cell accumulation and effector function. Our study thus highlights the complex interplay of TNF-based regulation of NK cells by the two TNF receptors during inflammation.
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MESH Headings
- Animals
- Killer Cells, Natural/immunology
- Receptors, Tumor Necrosis Factor, Type I/metabolism
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Receptors, Tumor Necrosis Factor, Type II/metabolism
- Receptors, Tumor Necrosis Factor, Type II/genetics
- Signal Transduction
- Inflammation/immunology
- Inflammation/metabolism
- Mice
- Mice, Inbred C57BL
- Hepatitis A Virus Cellular Receptor 2/metabolism
- Hepatitis A Virus Cellular Receptor 2/genetics
- Salmonella typhimurium/immunology
- Mice, Knockout
- Salmonella Infections/immunology
- Tumor Necrosis Factor-alpha/metabolism
- Male
- Female
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Affiliation(s)
- Timothy R McCulloch
- Frazer Institute, The University of Queensland, Woolloongabba, Australia.
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany.
| | - Gustavo R Rossi
- Frazer Institute, The University of Queensland, Woolloongabba, Australia
| | - Louisa Alim
- Frazer Institute, The University of Queensland, Woolloongabba, Australia
| | - Pui Yeng Lam
- Frazer Institute, The University of Queensland, Woolloongabba, Australia
| | - Joshua K M Wong
- Frazer Institute, The University of Queensland, Woolloongabba, Australia
| | - Elaina Coleborn
- Frazer Institute, The University of Queensland, Woolloongabba, Australia
| | - Snehlata Kumari
- Frazer Institute, The University of Queensland, Woolloongabba, Australia
| | - Colm Keane
- Frazer Institute, The University of Queensland, Woolloongabba, Australia
- Princess Alexandra Hospital, Woolloongabba, Australia
| | - Andrew J Kueh
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Marco J Herold
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
| | - Christoph Wilhelm
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Percy A Knolle
- Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Lawrence Kane
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Timothy J Wells
- Frazer Institute, The University of Queensland, Woolloongabba, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia
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20
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Tan S, Qi C, Zeng H, Wei Q, Huang Q, Pu X, Li W, Li Y, Tian P. Steroid-Refractory Myocarditis Induced by Immune Checkpoint Inhibitor Responded to Infliximab: Report of Two Cases and Literature Review. Cardiovasc Toxicol 2024; 24:1174-1191. [PMID: 39256296 PMCID: PMC11445312 DOI: 10.1007/s12012-024-09918-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 09/02/2024] [Indexed: 09/12/2024]
Abstract
Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 and its ligand (PD-1/PD-L1) as well as anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), have been widely used for treating solid tumors. Myocarditis is a potentially lethal immune-related adverse events (irAEs) caused by ICIs therapy. The treatment of steroid-refractory myocarditis is challenging. We reported two non-small-cell lung cancer patients with steroid-refractory myocarditis induced by ICI. The symptoms were not resolved after pulse corticosteroid therapy and subsequent treatment including intravenous immunoglobulin and mycophenolate mofetil. Considering the level of serum interleukin (IL)-6 decreased by > 50% and level of serum tumor necrosis factor-α (TNF-α) increased during the course of the disease, infliximab was used. Myocarditis gradually alleviated after infliximab treatment. The cases revealed that specific cytokine inhibitors have promising roles in the treatment of steroid-refractory myocarditis. Infliximab could be considered for patients with low level of IL-6 and elevated level of TNF-α.
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Affiliation(s)
- Sihan Tan
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, Sichuan, China
| | - Chang Qi
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, Sichuan, China
| | - Hao Zeng
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, Sichuan, China
| | - Qi Wei
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, Sichuan, China
| | - Qin Huang
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, Sichuan, China
| | - Xin Pu
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, Sichuan, China
| | - Weimin Li
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yalun Li
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, Sichuan, China.
| | - Panwen Tian
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, Sichuan, China.
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21
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Shi W, Liu N, Lu H. Advancements and challenges in immunocytokines: A new arsenal against cancer. Acta Pharm Sin B 2024; 14:4649-4664. [PMID: 39664443 PMCID: PMC11628837 DOI: 10.1016/j.apsb.2024.07.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/20/2024] [Accepted: 07/27/2024] [Indexed: 12/13/2024] Open
Abstract
Immunocytokines, employing targeted antibodies to concentrate cytokines at tumor sites, have shown potential advantages such as prolonged cytokine half-lives, mitigated adverse effects, and synergistic antitumor efficacy from both antibody and cytokine components. First, we present an in-depth analysis of the advancements of immunocytokines evaluated in preclinical and clinical applications. Notably, anti-PD-1-based immunocytokines can redirect cytokines to intratumoral CD8+ T cells and reinvigorate them to elicit robust antitumor immune responses. Then, we focus on their molecular structures and action mechanisms, striving to elucidate the correlations between diverse molecular structures and their antitumor efficacy. Moreover, our exploration extends to the realm of novel cytokines, including IL-10, IL-18, and IL-24, unraveling their potential in the construction of immunocytokines. However, safety concerns remain substantial barriers to immunocytokines' development. To address this challenge, we explore potential strategies, such as cytokine engineering and prodrug design, which can foster next-generation immunocytokines development. Overall, this review concentrates on the design of molecular structures in immunocytokines, underscoring the direction and focus of ongoing efforts to improve safety profiles while maximizing therapeutic efficacy.
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Affiliation(s)
- Wenqiang Shi
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Nan Liu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Huili Lu
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
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22
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Jia Y, Wu Q, Yang Z, Sun R, Zhang K, Guo X, Xu R, Guo Y. Mechanisms of myocardial toxicity of antitumor drugs and potential therapeutic strategies: A review of the literature. Curr Probl Cardiol 2024; 49:102782. [PMID: 39134104 DOI: 10.1016/j.cpcardiol.2024.102782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/07/2024] [Indexed: 08/28/2024]
Abstract
With the successive development of chemotherapy drugs, good results have been achieved in clinical application. However, myocardial toxicity is the biggest challenge. Anthracyclines, immune checkpoint inhibitors, and platinum drugs are widely used. Targeted drug delivery, nanomaterials and dynamic imaging evaluation are all emerging research directions. This article reviews the recent literature on the use of targeted nanodrug delivery and imaging techniques to evaluate the myocardial toxicity of antineoplastic drugs, and discusses the potential mechanisms.
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Affiliation(s)
- Yang Jia
- Department of Radiology, West China Second University Hospital, Sichuan University, 20# South Renmin Road, Chengdu, Sichuan 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education; 20# South Renmin Road, Chengdu, Sichuan 610041, China
| | - Qihong Wu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education; 20# South Renmin Road, Chengdu, Sichuan 610041, China
| | - Zhigang Yang
- Department of Radiology, West China Hospital, Sichuan University, No. 37 Guoxue Street, Chengdu 610041, China
| | - Ran Sun
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education; 20# South Renmin Road, Chengdu, Sichuan 610041, China
| | - Kun Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education; 20# South Renmin Road, Chengdu, Sichuan 610041, China
| | - Xia Guo
- Department of Hematology, West China Second University Hospital, Sichuan University; 20# South Renmin Road, Chengdu, Sichuan 610041, China
| | - Rong Xu
- Department of Radiology, West China Second University Hospital, Sichuan University, 20# South Renmin Road, Chengdu, Sichuan 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education; 20# South Renmin Road, Chengdu, Sichuan 610041, China.
| | - Yingkun Guo
- Department of Radiology, West China Second University Hospital, Sichuan University, 20# South Renmin Road, Chengdu, Sichuan 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education; 20# South Renmin Road, Chengdu, Sichuan 610041, China.
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23
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Chen Q, Zheng X, Cheng W, Li J. Landscape of targeted therapies for lung squamous cell carcinoma. Front Oncol 2024; 14:1467898. [PMID: 39544292 PMCID: PMC11560903 DOI: 10.3389/fonc.2024.1467898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/08/2024] [Indexed: 11/17/2024] Open
Abstract
Lung cancer, a common type of malignant neoplasm, has seen significant advancements in the treatment of lung adenocarcinoma (LUAD). However, the management of lung squamous cell carcinoma (LSCC) continues to pose challenges. Traditional treatment methods for LSCC encompass surgical resection, chemotherapy, and radiotherapy. The introduction of targeted therapy and immunotherapy has greatly benefited LSCC patients, but issues such as limited immune response rates and adverse reactions persist. Therefore, gaining a deeper comprehension of the underlying mechanisms holds immense importance. This review provides an in-depth overview of classical signaling pathways and therapeutic targets, including the PI3K signaling pathway, CDK4/6 pathway, FGFR1 pathway and EGFR pathway. Additionally, we delve into alternative signaling pathways and potential targets that could offer new therapeutic avenues for LSCC. Lastly, we summarize the latest advancements in targeted therapy combined with immune checkpoint blockade (ICB) therapy for LSCC and discuss the prospects and challenges in this field.
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Affiliation(s)
- Qiuxuan Chen
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xiaoshuo Zheng
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Weiting Cheng
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jian Li
- Institude of Experimental Immunology, University Clinic of Rheinische Friedrich-Wihelms-University, Bonn, Germany
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24
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Barbir EB, Kitchlu A, Herrmann SM. Immune checkpoint inhibitor-associated nephritis-treatment standard. Nephrol Dial Transplant 2024; 39:1785-1798. [PMID: 39138117 DOI: 10.1093/ndt/gfae184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Indexed: 08/15/2024] Open
Abstract
Over the last 13 years, the use of immune checkpoint inhibitor (ICI) therapy has grown remarkably, owing to their unprecedented anti-tumor efficacy in certain tumor groups. With increased use of ICIs, we are seeing immune-related adverse events (irAEs) more frequently. Renal irAEs, such as ICI-associated acute kidney injury (ICI-AKI), are reported in 2%-5% of patients treated with ICIs, with acute tubulointerstitial nephritis (ATIN) as the most common histopathologic lesion, though various forms of glomerulonephritis have also been reported. Modifiable risk factors for ICI-AKI include concurrent use of ATIN-associated drugs, like proton pump inhibitors, non-steroidal anti-inflammatory drugs and antibiotics, and dual ICI therapy with both Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) and Programmed Cell Death Protein 1 and its ligand (PD1/PDL-1) blockade. Kidney biopsies remain the diagnostic modality of choice, though several promising non-invasive biomarkers, which have not yet been broadly clinically validated have emerged. The treatment of ICI-AKI involves holding ICIs, discontinuation of ATIN-associated drugs and initiation of immunosuppression with corticosteroids as first-line therapy. With prompt treatment initiation, most patients achieve full or partial renal recovery, allowing for re-challenge with ICI. However, a subset of patients will require additional steroid-sparing therapies for corticosteroid-dependent or refractory ICI-AKI. Here we review developments in our understanding of the pathophysiology of ICI-AKI, the approach to diagnosis (with a focus on the emergence of novel diagnostic tools), prognostic factors and the current evidence for establishing treatment standards for ICI-AKI. As the evidence base remains largely retrospective, we identify questions that would benefit from future prospective studies in the diagnosis, management and prognostication of ICI-AKI.
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Affiliation(s)
- Elena-Bianca Barbir
- Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Abhijat Kitchlu
- Department of Medicine, Division of Nephrology, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Sandra M Herrmann
- Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
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25
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Zoghbi M, Burk KJ, Haroun E, Saade M, Carreras MTC. Immune checkpoint inhibitor-induced diarrhea and colitis: an overview. Support Care Cancer 2024; 32:680. [PMID: 39311981 PMCID: PMC11420271 DOI: 10.1007/s00520-024-08889-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have emerged as an integral component of the management of various cancers and have contributed to significant improvements in overall survival. Most available ICIs target anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4), and anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD1/PDL1). Gastrointestinal immune-related adverse events remain a common complication of ICIs. The predominant manifestations include diarrhea and colitis, which often manifest concurrently as immune-mediated diarrhea and colitis (IMDC). Risk factors for developing these side effects include baseline gut microbiota, preexisting autoimmune disorders, such as inflammatory bowel disease, and type of neoplasm. The hallmark symptom of colitis is diarrhea which may be accompanied by mucus or blood in stools. Patients may also experience abdominal pain, fever, vomiting, and nausea. If not treated rapidly, ICI-induced colitis can lead to serious life-threatening complications. Current management is based on corticosteroids as first-line, and immunosuppressants like infliximab or vedolizumab for refractory cases. Microbiota transplantation and specific cytokines and lymphocyte replication inhibitors are being investigated. Optimal patient care requires maintaining a balance between treatment toxicity and efficacy, hence the aim of this review is to enhance readers' comprehension of the gastrointestinal adverse events associated with ICIs, particularly IMDC. In addition to identifying the risk factors, we discuss the incidence, clinical presentation, workup, and management options of IMDC.
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Affiliation(s)
- Marianne Zoghbi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Kathryn J Burk
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elio Haroun
- Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1100, Lebanon
| | - Maria Saade
- Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1100, Lebanon
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26
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Valenzuela-Cardenas M, Fisher C, Bartee MY, Bartee E. IL-12-mediated toxicity from localized oncolytic virotherapy can be reduced using systemic TNF blockade. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200866. [PMID: 39290317 PMCID: PMC11407086 DOI: 10.1016/j.omton.2024.200866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/23/2024] [Accepted: 08/23/2024] [Indexed: 09/19/2024]
Abstract
Cytokine therapy represents an attractive option to improve the outcomes of cancer patients. However, the systemic delivery of these agents often leads to severe immune-related toxicities, which can prevent their efficient clinical use. One approach to address this issue is the use of recombinant oncolytic viruses to deliver various cytokines directly to the tumor. This improves the biodistribution of the secreted cytokine-transgenes, both augmenting antitumor immune responses and decreasing systemic toxicities. We have shown recently that a doubly recombinant oncolytic myxoma virus that secretes a soluble version of PD1 as well as an interleukin-12 (IL-12) fusion protein (vPD1/IL-12) can cause potent regression of disseminated cancers. Here we show that, despite the predominant localization of both transgenes within the infected tumor, treatment with vPD1/IL-12 still results in systemic, IL-12-mediated toxicities. Interestingly, these toxicities are independent of interferon-γ and instead appear to be mediated by the interaction of tumor necrosis factor α with tumor necrosis factor receptor 2 on hematopoietic cells. Critically, this unique mechanism allows for vPD1/IL-12-mediated toxicities to be alleviated through the use of US Food and Drug Administration (FDA)-approved tumor necrosis factor (TNF) blockers such as etanercept.
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Affiliation(s)
| | - Carrie Fisher
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Mee Y Bartee
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Eric Bartee
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
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27
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Alam MS, Gaida MM, Witzel HR, Otsuka S, Abbasi A, Guerin T, Abdelmaksoud A, Wong N, Cam MC, Kozlov S, Ashwell JD. TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function. Cell Rep Med 2024; 5:101696. [PMID: 39178856 PMCID: PMC11528236 DOI: 10.1016/j.xcrm.2024.101696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/28/2024] [Accepted: 07/30/2024] [Indexed: 08/26/2024]
Abstract
Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DCs). Here, we find that genetic ablation or antibody blockade of tumor necrosis factor receptor 1 (TNFR1) enhanced intratumor T cell activation and slowed PDAC growth. While anti-PD-1 checkpoint inhibition alone had little effect, it further enhanced intratumor T cell activation in combination with anti-TNFR1. The major cellular alteration in the tumor microenvironment in the absence of TNFR1 signaling was a large increase in DC number and immunostimulatory phenotype. This may reflect a direct effect on DCs, because TNF induced TNFR1-dependent apoptosis of bone-marrow-derived DCs. The therapeutic response to anti-TNFR1 alone was superior to the combination of DC-activating agonistic anti-CD40 and Flt3 ligand (Flt3L). These observations suggest that targeting TNFR1, perhaps in concert with other strategies that promote DC generation and mobilization, may have therapeutic benefits.
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Affiliation(s)
- Muhammad S Alam
- Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Matthias M Gaida
- Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany; TRON, Translational Oncology at the University Medical Center, JGU-Mainz, 55131 Mainz, Germany; Research Center for Immunotherapy, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany
| | - Hagen R Witzel
- Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany
| | - Shizuka Otsuka
- Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Aamna Abbasi
- Department of Integrative Immunobiology, Duke University, Durham, NC 27708, USA
| | - Theresa Guerin
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21707, USA
| | - Abdalla Abdelmaksoud
- Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Nathan Wong
- Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Margaret C Cam
- Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Serguei Kozlov
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21707, USA
| | - Jonathan D Ashwell
- Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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28
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Kao CJ, Charmsaz S, Alden SL, Brancati M, Li HL, Balaji A, Munjal K, Howe K, Mitchell S, Leatherman J, Griffin E, Nakazawa M, Tsai HL, Danilova L, Thoburn C, Gizzi J, Gross NE, Hernandez A, Coyne EM, Shin SM, Babu JS, Apostol GW, Durham J, Christmas BJ, Konig MF, Lipson EJ, Naidoo J, Cappelli LC, Pabani A, Ged Y, Baretti M, Brahmer J, Hoffman-Censits J, Seiwert TY, Garonce-Hediger R, Guha A, Bansal S, Tang L, Jaffee EM, Chandler GS, Mohindra R, Ho WJ, Yarchoan M. Immune-related events in individuals with solid tumors on immunotherapy associate with Th17 and Th2 signatures. J Clin Invest 2024; 134:e176567. [PMID: 39403935 PMCID: PMC11473156 DOI: 10.1172/jci176567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 08/20/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUNDImmune-related adverse events (irAEs) and their associated morbidity/mortality are a key concern for patients receiving immune checkpoint inhibitors (ICIs). Prospective evaluation of the drivers of irAEs in a diverse pan-tumor cohort is needed to identify patients at greatest risk and to develop rational treatment and interception strategies.METHODSIn an observational study, we prospectively collected blood samples and performed regular clinical evaluations for irAEs in patients receiving ICI therapy as standard of care for solid tumors. We performed in-parallel analysis of cytokines by Luminex immunoassay and circulating immune cells by cytometry by time-of-flight (CyTOF) at baseline and on treatment to investigate mechanisms of irAEs.RESULTSWe enrolled 111 patients, of whom 40.5% developed a symptomatic irAE (grade ≥ 2). Development of a grade ≥ 2 irAE was positively associated with the use of combination ICI and a history of an autoimmune disorder. Early changes in T helper 17 (Th17) (IL-6, IL-17f), type 2 (IL-5, IL-13, IL-25), and type 1 (TNF-α) cytokine signatures and congruent on-treatment expansions of Th17 and Th2 effector memory (Th2EM) T cell populations in peripheral blood were positively associated with the development of grade ≥2 irAEs. IL-6 levels were also associated with inferior cancer-specific survival and overall survival.CONCLUSIONSIn a diverse, prospective pan-tumor cohort, Th17 and Th2 skewing during early ICI treatment was associated with the development of clinically relevant irAEs but not antitumor responses, providing possible targets for monitoring and therapeutic interventions.FUNDINGJohns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, the NCI SPORE in Gastrointestinal Cancers (P50 CA062924), NCI grant (R50CA243627 to LD), the NIH Center Core Grant (P30 CA006973), Swim Across America (to MY), NIAMS (K23AR075872 to LC), and imCORE-Genentech grant 137515 (to Johns Hopkins Medicine on behalf of MY).
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Affiliation(s)
- Chester J. Kao
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Soren Charmsaz
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | | | - Madelena Brancati
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Howard L. Li
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Aanika Balaji
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kabeer Munjal
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Kathryn Howe
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Sarah Mitchell
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - James Leatherman
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Ervin Griffin
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Mari Nakazawa
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Hua-Ling Tsai
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ludmila Danilova
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Convergence Institute and
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Chris Thoburn
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jennifer Gizzi
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Nicole E. Gross
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Alexei Hernandez
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Erin M. Coyne
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Sarah M. Shin
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Jayalaxmi Suresh Babu
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - George W. Apostol
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Jennifer Durham
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Brian J. Christmas
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
| | - Maximilian F. Konig
- Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Evan J. Lipson
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jarushka Naidoo
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Beaumont Hospital, Dublin, Ireland
- RCSI University of Health Sciences, Dublin, Ireland
| | - Laura C. Cappelli
- Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Aliyah Pabani
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Yasser Ged
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Marina Baretti
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Julie Brahmer
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Jean Hoffman-Censits
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tanguy Y. Seiwert
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Aditi Guha
- Genentech Inc., a member of the imCORE network, South San Francisco, California, USA
| | - Sanjay Bansal
- Genentech Inc., a member of the imCORE network, South San Francisco, California, USA
| | - Laura Tang
- Genentech Inc., a member of the imCORE network, South San Francisco, California, USA
| | - Elizabeth M. Jaffee
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Convergence Institute and
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - G. Scott Chandler
- F. Hoffmann-La Roche Ltd., a member of the imCORE network, Basel, Switzerland
| | - Rajat Mohindra
- F. Hoffmann-La Roche Ltd., a member of the imCORE network, Basel, Switzerland
| | - Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Convergence Institute and
| | - Mark Yarchoan
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Convergence Institute and
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
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29
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Öhnstedt E, Doñas C, Parv K, Pang Y, Lofton Tomenius H, Carrasco López M, Gannavarapu VR, Choi J, Ovezik M, Frank P, Jorvid M, Roos S, Vågesjö E, Phillipson M. Oral administration of CXCL12-expressing Limosilactobacillus reuteri improves colitis by local immunomodulatory actions in preclinical models. Am J Physiol Gastrointest Liver Physiol 2024; 327:G140-G153. [PMID: 38780469 DOI: 10.1152/ajpgi.00022.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 05/25/2024]
Abstract
Treatments of colitis, inflammation of the intestine, rely on induction of immune suppression associated with systemic adverse events, including recurrent infections. This treatment strategy is specifically problematic in the increasing population of patients with cancer with immune checkpoint inhibitor (ICI)-induced colitis, as immune suppression also interferes with the ICI-treatment response. Thus, there is a need for local-acting treatments that reduce inflammation and enhance intestinal healing. Here, we investigated the effect and safety of bacterial delivery of short-lived immunomodulating chemokines to the inflamed intestine in mice with colitis. Colitis was induced by dextran sulfate sodium (DSS) alone or in combination with ICI (anti-PD1 and anti-CTLA-4), and Limosilactobacillus reuteri R2LC (L. reuteri R2LC) genetically modified to express the chemokine CXCL12-1α (R2LC_CXCL12, emilimogene sigulactibac) was given perorally. In addition, the pharmacology and safety of the formulated drug candidate, ILP100-Oral, were evaluated in rabbits. Peroral CXCL12-producing L. reuteri R2LC significantly improved colitis symptoms already after 2 days in mice with overt DSS and ICI-induced colitis, which in benchmarking experiments was demonstrated to be superior to treatments with anti-TNF-α, anti-α4β7, and corticosteroids. The mechanism of action involved chemokine delivery to Peyer's patches (PPs), confirmed by local CXCR4 signaling, and increased numbers of colonic, regulatory immune cells expressing IL-10 and TGF-β1. No systemic exposure or engraftment could be detected in mice, and product feasibility, pharmacology, and safety were confirmed in rabbits. In conclusion, peroral CXCL12-producing L. reuteri R2LC efficiently ameliorates colitis, enhances mucosal healing, and has a favorable safety profile.NEW & NOTEWORTHY Colitis symptoms are efficiently reduced by peroral administration of probiotic bacteria genetically modified to deliver CXCL12 locally to the inflamed intestine in several mouse models.
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Affiliation(s)
- Emelie Öhnstedt
- Ilya Pharma AB, Uppsala, Sweden
- Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | | | | | | | - Hava Lofton Tomenius
- Ilya Pharma AB, Uppsala, Sweden
- Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | | | - Venkata Ram Gannavarapu
- Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Jacqueline Choi
- Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Maria Ovezik
- Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | | | | | - Stefan Roos
- Department of Molecular Sciences, Swedish University of Agriculture, Uppsala, Sweden
| | - Evelina Vågesjö
- Ilya Pharma AB, Uppsala, Sweden
- Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Mia Phillipson
- Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- The Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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30
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Verheijden RJ, Burgers FH, Janssen JC, Putker AE, Veenstra SPGR, Hospers GAP, Aarts MJB, Hehenkamp KW, Doornebosch VLE, Verhaert M, van den Berkmortel FWPJ, Chatzidionysiou K, Llobell A, Barros M, Maria ATJ, Takeji A, García Morillo JS, Lidar M, van Eijs MJM, Blank CU, Aspeslagh S, Piersma D, Kapiteijn E, Labots M, Boers-Sonderen MJ, van der Veldt AAM, Haanen JBAG, May AM, Suijkerbuijk KPM. Corticosteroids and other immunosuppressants for immune-related adverse events and checkpoint inhibitor effectiveness in melanoma. Eur J Cancer 2024; 207:114172. [PMID: 38905818 DOI: 10.1016/j.ejca.2024.114172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 05/30/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs. METHODS Patients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression. RESULTS Among 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4-8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4-14) and 55 (95 %CI 41-not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HRadj 1.14; 95 %CI 1.01-1.29; HRadj 1.29; 95 %CI 1.12-1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HRadj 1.32; 95 %CI 1.02-1.72) and OS (HRadj 1.34; 95 %CI 0.99-1.82) compared with corticosteroids alone. CONCLUSIONS High corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment.
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Affiliation(s)
- Rik J Verheijden
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Femke H Burgers
- Divisions of Medical Oncology & Molecular Oncology & Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands
| | - Josephine C Janssen
- Department of Medical Oncology and Surgical Oncology, Erasmus Medical Centre, 's Gravendijkwal 230, 3015CE Rotterdam, the Netherlands
| | - Anouk E Putker
- Department of Medical Oncology, Radboud University Medical Centre, Geert Grooteplein Zuid 10, 6525GA Nijmegen, the Netherlands
| | - Sophie P G R Veenstra
- Department of Medical Oncology, Amsterdam UMC location VUmc, Cancer Center Amsterdam, De Boelelaan 1117, 1081HV Amsterdam, the Netherlands
| | - Geke A P Hospers
- Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
| | - Maureen J B Aarts
- Department of Medical Oncology, GROW-School for Oncology and Reproduction, Maastricht University Medical Centre+, P. Debyelaan 25, 6229HX Maastricht, the Netherlands
| | - Karel W Hehenkamp
- Department of Medical Oncology, Leiden University Medical Centre, Albinusdreef 2, 2333ZA Leiden, the Netherlands
| | - Veerle L E Doornebosch
- Department of Internal Medicine, Medisch Spectrum Twente, Koningsplein 1, 7512KZ Enschede, the Netherlands
| | - Marthe Verhaert
- Department of Medical Oncology, Laboratory of Medical and Molecular Oncology (LMM0), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Jette, Belgium
| | | | | | - Arturo Llobell
- R3 Rheumatology, Parc Taulí University Hospital, Sabadell, Barcelona 1-08208, Spain
| | - Milton Barros
- Department of Clinical Oncology, AC Camargo Cancer Center, R. Professor Antônio Prudente, 211 Liberdade, Sao Paulo, Brazil
| | - Alexandre T J Maria
- Department of Internal Medicine, CHRU de Montpellier, 371 avenue du Doyen Gaston Giraud, 34090 Montpellier, France
| | - Akari Takeji
- Division of Rheumatology, Kanazawa University Hospital, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan
| | - José-Salvador García Morillo
- Unidad de Enfermedades Autoinmunes Sistemicas y Raras del Adulto, UGC Medicina Interna, Hospital Universitario Virgen del Rocío, Avda de Manuel Siurot s/n., 41013 Sevilla, Spain
| | - Merav Lidar
- Rheumatology Unit, Sheba Medical Center, Derech Sheba 2, Tel HaShomer, Israel
| | - Mick J M van Eijs
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Lundlaan 6, 3584EA Utrecht, the Netherlands
| | - Christian U Blank
- Department of Medical Oncology & Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands
| | - Sandrine Aspeslagh
- Department of Medical Oncology, Laboratory of Medical and Molecular Oncology (LMM0), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Jette, Belgium
| | - Djura Piersma
- Department of Internal Medicine, Medisch Spectrum Twente, Koningsplein 1, 7512KZ Enschede, the Netherlands
| | - Ellen Kapiteijn
- Department of Medical Oncology, Leiden University Medical Centre, Albinusdreef 2, 2333ZA Leiden, the Netherlands
| | - Mariette Labots
- Department of Medical Oncology, Amsterdam UMC location VUmc, Cancer Center Amsterdam, De Boelelaan 1117, 1081HV Amsterdam, the Netherlands
| | - Marye J Boers-Sonderen
- Department of Medical Oncology, Radboud University Medical Centre, Geert Grooteplein Zuid 10, 6525GA Nijmegen, the Netherlands
| | - Astrid A M van der Veldt
- Department of Medical Oncology and Radiology & Nuclear Medicine, Erasmus Medical Centre, 's Gravendijkwal 230, 3015CE Rotterdam, the Netherlands
| | - John B A G Haanen
- Divisions of Medical Oncology & Molecular Oncology & Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Department of Medical Oncology, Leiden University Medical Centre, Albinusdreef 2, 2333ZA Leiden, the Netherlands; Melanoma clinic, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 23, 1011 Lausanne, Switzerland
| | - Anne M May
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Karijn P M Suijkerbuijk
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands.
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31
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Dufau C, Genais M, Mucher E, Jung B, Garcia V, Montfort A, Tosolini M, Clarke CJ, Medin JA, Levade T, Delord JP, Meyer N, Pancaldi V, Andrieu-Abadie N, Ségui B. Ceramide metabolism alterations contribute to Tumor Necrosis Factor-induced melanoma dedifferentiation and predict resistance to immune checkpoint inhibitors in advanced melanoma patients. Front Immunol 2024; 15:1421432. [PMID: 39136013 PMCID: PMC11317267 DOI: 10.3389/fimmu.2024.1421432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 07/08/2024] [Indexed: 08/15/2024] Open
Abstract
Introduction Advanced cutaneous melanoma is a skin cancer characterized by a poor prognosis and high metastatic potential. During metastatic spread, melanoma cells often undergo dedifferentiation toward an invasive phenotype, resulting in reduced expression of microphthalmia-associated transcription factor (MITF)-dependent melanoma antigens and facilitating immune escape. Tumor Necrosis Factor (TNF) is known to be a key factor in melanoma dedifferentiation. Interestingly, accumulating evidence suggests that TNF may play a role in melanoma progression and resistance to immunotherapies. Additionally, TNF has been identified as a potent regulator of sphingolipid metabolism, which could contribute to melanoma aggressiveness and the process of melanoma dedifferentiation. Methods We conducted RNA sequencing and mass spectrometry analyses to investigate TNF-induced dedifferentiation in two melanoma cell lines. In vitro experiments were performed to manipulate sphingolipid metabolism using genetic or pharmacologic alterations in combination with TNF treatment, aiming to elucidate the potential involvement of this metabolism in TNF-induced dedifferentiation. Lastly, to evaluate the clinical significance of our findings, we performed unsupervised analysis of plasma sphingolipid levels in 48 patients receiving treatment with immune checkpoint inhibitors, either alone or in combination with anti-TNF therapy. Results Herein, we demonstrate that TNF-induced melanoma cell dedifferentiation is associated with a global modulation of sphingolipid metabolism. Specifically, TNF decreases the expression and activity of acid ceramidase (AC), encoded by the ASAH1 gene, while increasing the expression of glucosylceramide synthase (GCS), encoded by the UGCG gene. Remarkably, knockdown of AC alone via RNA interference is enough to induce melanoma cell dedifferentiation. Furthermore, treatment with Eliglustat, a GCS inhibitor, inhibits TNF-induced melanoma cell dedifferentiation. Lastly, analysis of plasma samples from patients treated with immune checkpoint inhibitors, with or without anti-TNF therapy, revealed significant predictive sphingolipids. Notably, the top 8 predictive sphingolipids, including glycosphingolipids, were associated with a poor response to immunotherapy. Discussion Our study highlights that ceramide metabolism alterations are causally involved in TNF-induced melanoma cell dedifferentiation and suggests that the evolution of specific ceramide metabolites in plasma may be considered as predictive biomarkers of resistance to immunotherapy.
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Affiliation(s)
- Carine Dufau
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Équipe labellisée Fondation Association (ARC), Toulouse, France
| | - Matthieu Genais
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Équipe labellisée Fondation Association (ARC), Toulouse, France
| | - Elodie Mucher
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Équipe labellisée Fondation Association (ARC), Toulouse, France
| | - Benjamin Jung
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Équipe labellisée Fondation Association (ARC), Toulouse, France
| | - Virginie Garcia
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Équipe labellisée Fondation Association (ARC), Toulouse, France
| | - Anne Montfort
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Équipe labellisée Fondation Association (ARC), Toulouse, France
| | - Marie Tosolini
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Équipe labellisée Fondation Association (ARC), Toulouse, France
| | - Christopher J. Clarke
- Stony Brook Cancer Center, and Department of Medicine, Stony Brook University, New York, NY, United States
| | - Jeffrey A. Medin
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Thierry Levade
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Équipe labellisée Fondation Association (ARC), Toulouse, France
- Laboratoire de Biochimie, Institut Fédératif de Biologie, Centre Hospitalier Universitaire (CHU) Purpan, Toulouse, France
| | - Jean-Pierre Delord
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Oncopole Claudius Regaud, Toulouse, France
| | - Nicolas Meyer
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Équipe labellisée Fondation Association (ARC), Toulouse, France
- Service d’Oncodermatologie, Institut Universitaire du Cancer (IUCT-O), Centre Hospitalier Universitaire (CHU) de Toulouse, Toulouse, France
| | - Vera Pancaldi
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
| | - Nathalie Andrieu-Abadie
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Équipe labellisée Fondation Association (ARC), Toulouse, France
| | - Bruno Ségui
- Unité Mixte de Recherche Intitut National de la Santé et de la Recherche Médicale (INSERM) 1037, Centre National de la Recherche Scientifique (CNRS) 5071, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, France
- Équipe labellisée Fondation Association (ARC), Toulouse, France
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Yi M, Li T, Niu M, Zhang H, Wu Y, Wu K, Dai Z. Targeting cytokine and chemokine signaling pathways for cancer therapy. Signal Transduct Target Ther 2024; 9:176. [PMID: 39034318 PMCID: PMC11275440 DOI: 10.1038/s41392-024-01868-3] [Citation(s) in RCA: 64] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/30/2024] [Accepted: 05/11/2024] [Indexed: 07/23/2024] Open
Abstract
Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and overcome resistance to conventional therapies. In this review, we summarized the current understanding and therapeutic implications of targeting cytokine and chemokine signaling pathways in cancer. By exploring the roles of these molecules in tumor biology and the immune response, we highlighted the development of novel therapeutic agents aimed at modulating these pathways to combat cancer. The review elaborated on the dual nature of cytokines as both promoters and suppressors of tumorigenesis, depending on the context, and discussed the challenges and opportunities this presents for therapeutic intervention. We also examined the latest advancements in targeted therapies, including monoclonal antibodies, bispecific antibodies, receptor inhibitors, fusion proteins, engineered cytokine variants, and their impact on tumor growth, metastasis, and the tumor microenvironment. Additionally, we evaluated the potential of combining these targeted therapies with other treatment modalities to overcome resistance and improve patient outcomes. Besides, we also focused on the ongoing research and clinical trials that are pivotal in advancing our understanding and application of cytokine- and chemokine-targeted therapies for cancer patients.
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Affiliation(s)
- Ming Yi
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Tianye Li
- Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, People's Republic of China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Haoxiang Zhang
- Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, 350001, People's Republic of China
| | - Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
| | - Zhijun Dai
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, People's Republic of China.
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Grice S, Olsson-Brown A, Naisbitt DJ, Hammond S. Immunological Drug-Drug Interactions Affect the Efficacy and Safety of Immune Checkpoint Inhibitor Therapies. Chem Res Toxicol 2024; 37:1086-1103. [PMID: 38912648 PMCID: PMC11256900 DOI: 10.1021/acs.chemrestox.4c00067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 06/02/2024] [Accepted: 06/07/2024] [Indexed: 06/25/2024]
Abstract
With the rapid expansion in the development and clinical utility of immune checkpoint inhibitors (ICIs) for oncology, the continual evaluation of the safety profile of such agents is imperative. The safety profile of ICIs as monotherapy is dominated by immune-related adverse events, which can be considered as an extension of the mechanism of action of these immunomodulatory drugs. Further to this, an emerging theme is that ICI treatment can significantly impact upon the tolerability of coadministered medications. Numerous reports in literature indicate that ICIs may alter the immunological perception of coadministered drugs, resulting in undesirable reactions to a variety of concomitant medications. These reactions can be severe in manifestation, including hepatotoxicity and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), but may also have detrimental impact on malignancy control. To minimize the impact of such drug-drug interactions on patients, it is imperative to identify medications that may cause these reactions, understand the underlying mechanisms, consider the timing and dosing of comedication, and explore alternative medications with comparable efficacies. Improving our understanding of how concomitant medications affect the safety and efficacy of ICIs can allow for potential culprit drugs to be identified/removed/desensitized. This approach will allow the continuation of ICI therapy that may have been discontinued otherwise, thereby improving malignant control and patient and drug development outcomes.
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Affiliation(s)
- Sophie Grice
- Department
of Molecular and Clinical Pharmacology, Institute of Translational
Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
| | - Anna Olsson-Brown
- Department
of Molecular and Clinical Pharmacology, Institute of Translational
Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
- Sussex
Cancer Centre, University Hospitals Sussex, Brighton BN2 5BD, U.K.
| | - Dean J. Naisbitt
- Department
of Molecular and Clinical Pharmacology, Institute of Translational
Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
| | - Sean Hammond
- Department
of Molecular and Clinical Pharmacology, Institute of Translational
Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
- ApconiX, Alderley Edge SK10 4TG, U.K.
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Oatman N, Gawali MV, Congrove S, Caceres R, Sukumaran A, Gupta N, Murugesan N, Arora P, Subramanian SV, Choi K, Abdel-Malek Z, Reisz JA, Stephenson D, Amaravadi R, Desai P, D’Alessandro A, Komurov K, Dasgupta B. A Multimodal Drug-Diet-Immunotherapy Combination Restrains Melanoma Progression and Metastasis. Cancer Res 2024; 84:2333-2351. [PMID: 38885087 PMCID: PMC11250569 DOI: 10.1158/0008-5472.can-23-1635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 02/12/2024] [Accepted: 05/08/2024] [Indexed: 06/20/2024]
Abstract
The genetic landscape of cancer cells can lead to specific metabolic dependencies for tumor growth. Dietary interventions represent an attractive strategy to restrict the availability of key nutrients to tumors. In this study, we identified that growth of a subset of melanoma was severely restricted by a rationally designed combination therapy of a stearoyl-CoA desaturase (SCD) inhibitor with an isocaloric low-oleic acid diet. Despite its importance in oncogenesis, SCD underwent monoallelic codeletion along with PTEN on chromosome 10q in approximately 47.5% of melanoma, and the other SCD allele was methylated, resulting in very low-SCD expression. Although this SCD-deficient subset was refractory to SCD inhibitors, the subset of PTEN wild-type melanoma that retained SCD was sensitive. As dietary oleic acid could potentially blunt the effect of SCD inhibitors, a low oleic acid custom diet was combined with an SCD inhibitor. The combination reduced monounsaturated fatty acids and increased saturated fatty acids, inducing robust apoptosis and growth suppression and inhibiting lung metastasis with minimal toxicity in preclinical mouse models of PTEN wild-type melanoma. When combined with anti-PD1 immunotherapy, the SCD inhibitor improved T-cell functionality and further constrained melanoma growth in mice. Collectively, these results suggest that optimizing SCD inhibitors with diets low in oleic acid may offer a viable and efficacious therapeutic approach for improving melanoma treatment. Significance: Blockade of endogenous production of fatty acids essential for melanoma combined with restriction of dietary intake blocks tumor growth and enhances response to immunotherapy, providing a rational drug-diet treatment regimen for melanoma.
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Affiliation(s)
- Nicole Oatman
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Mruniya V. Gawali
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Sunny Congrove
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Roman Caceres
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Abitha Sukumaran
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Nishtha Gupta
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Narmadha Murugesan
- Divisions of Molecular and Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Priyanka Arora
- College of Pharmacy, University of Cincinnati, Cincinnati, OH
| | | | - Kwangmin Choi
- Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | | | - Julie A. Reisz
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Daniel Stephenson
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Ravi Amaravadi
- Department of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
| | - Pankaj Desai
- College of Pharmacy, University of Cincinnati, Cincinnati, OH
| | - Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Kakajan Komurov
- Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Biplab Dasgupta
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- College of Medicine, Cincinnati, OH, United States
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Chen YH, Kovács T, Ferdinandy P, Varga ZV. Treatment options for immune-related adverse events associated with immune checkpoint inhibitors. Br J Pharmacol 2024. [PMID: 38803135 DOI: 10.1111/bph.16405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 02/14/2024] [Accepted: 03/09/2024] [Indexed: 05/29/2024] Open
Abstract
The immunotherapy revolution with the use of immune checkpoint inhibitors (ICIs) started with the clinical use of the first ICI, ipilimumab, in 2011. Since then, the field of ICI therapy has rapidly expanded - with the FDA approval of 10 different ICI drugs so far and their incorporation into the therapeutic regimens of a range of malignancies. While ICIs have shown high anti-cancer efficacy, they also have characteristic side effects, termed immune-related adverse events (irAEs). These side effects hinder the therapeutic potential of ICIs and, therefore, finding ways to prevent and treat them is of paramount importance. The current protocols to manage irAEs follow an empirical route of steroid administration and, in more severe cases, ICI withdrawal. However, this approach is not optimal in many cases, as there are often steroid-refractory irAEs, and there is a potential for corticosteroid use to promote tumour progression. This review surveys the current alternative approaches to the treatments for irAEs, with the goal of summarizing and highlighting the best attempts to treat irAEs, without compromising anti-tumour immunity and allowing for rechallenge with ICIs after resolution of the irAEs.
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Affiliation(s)
- Yu Hua Chen
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Tamás Kovács
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- HCEMM-SU Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - Zoltán V Varga
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- HCEMM-SU Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary
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Kachi S, Sumitomo S, Oka H, Hata A, Ohmura K. Case report: Inflammatory sternoclavicular joint arthritis induced by an immune checkpoint inhibitor with remarkable responsiveness to infliximab. Front Immunol 2024; 15:1400097. [PMID: 38799449 PMCID: PMC11116605 DOI: 10.3389/fimmu.2024.1400097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 04/25/2024] [Indexed: 05/29/2024] Open
Abstract
This report describes the case of a 48-year-old woman who presented with sternoclavicular joint arthritis after administration of an immune checkpoint inhibitor (ICI), durvalumab, for small cell lung carcinoma. The onset of arthritis transpired 18 months after the commencement of the ICI therapeutic regimen and demonstrated resilience to glucocorticoid treatment. After excluding infectious aetiologies and metastatic involvement, the patient was diagnosed with ICI-induced arthritis (ICI-IA). Considering the articular implications akin to the SAPHO syndrome, the patient was treated with infliximab, resulting in complete resolution. This finding implies that biological DMARDs can serve as effective interventions for ICI-induced sternoclavicular joint arthritis. Given the heterogeneous nature of its pathogenesis, the selection of therapeutic agents may require customization based on the distinct clinical presentation of each individual case.
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Affiliation(s)
- Shion Kachi
- Department of Rheumatology, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan
| | - Shuji Sumitomo
- Department of Rheumatology, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan
| | - Hideki Oka
- Department of Rheumatology, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan
| | - Akito Hata
- Department of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Kobe, Hyogo, Japan
| | - Koichiro Ohmura
- Department of Rheumatology, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan
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Ibrahim AA, Fujimura T, Uno T, Terada T, Hirano KI, Hosokawa H, Ohta A, Miyata T, Ando K, Yahata T. Plasminogen activator inhibitor-1 promotes immune evasion in tumors by facilitating the expression of programmed cell death-ligand 1. Front Immunol 2024; 15:1365894. [PMID: 38779680 PMCID: PMC11109370 DOI: 10.3389/fimmu.2024.1365894] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/23/2024] [Indexed: 05/25/2024] Open
Abstract
Background Increased levels of plasminogen activator inhibitor-1 (PAI-1) in tumors have been found to correlate with poor clinical outcomes in patients with cancer. Although abundant data support the involvement of PAI-1 in cancer progression, whether PAI-1 contributes to tumor immune surveillance remains unclear. The purposes of this study are to determine whether PAI-1 regulates the expression of immune checkpoint molecules to suppresses the immune response to cancer and demonstrate the potential of PAI-1 inhibition for cancer therapy. Methods The effects of PAI-1 on the expression of the immune checkpoint molecule programmed cell death ligand 1 (PD-L1) were investigated in several human and murine tumor cell lines. In addition, we generated tumor-bearing mice and evaluated the effects of a PAI-1 inhibitor on tumor progression or on the tumor infiltration of cells involved in tumor immunity either alone or in combination with immune checkpoint inhibitors. Results PAI-1 induces PD-L1 expression through the JAK/STAT signaling pathway in several types of tumor cells and surrounding cells. Blockade of PAI-1 impedes PD-L1 induction in tumor cells, significantly reducing the abundance of immunosuppressive cells at the tumor site and increasing cytotoxic T-cell infiltration, ultimately leading to tumor regression. The anti-tumor effect elicited by the PAI-1 inhibitor is abolished in immunodeficient mice, suggesting that PAI-1 blockade induces tumor regression by stimulating the immune system. Moreover, combining a PAI-1 inhibitor with an immune checkpoint inhibitor significantly increases tumor regression. Conclusions PAI-1 protects tumors from immune surveillance by increasing PD-L1 expression; hence, therapeutic PAI-1 blockade may prove valuable in treating malignant tumors.
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Affiliation(s)
- Abd Aziz Ibrahim
- Translational Molecular Therapeutics Laboratory, Division of Host Defense Mechanism, Tokai University School of Medicine, Kanagawa, Japan
| | - Taku Fujimura
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomoko Uno
- Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan
| | - Tomoya Terada
- Translational Molecular Therapeutics Laboratory, Division of Host Defense Mechanism, Tokai University School of Medicine, Kanagawa, Japan
| | - Ken-ichi Hirano
- Department of Immunology, Tokai University School of Medicine, Kanagawa, Japan
| | - Hiroyuki Hosokawa
- Department of Immunology, Tokai University School of Medicine, Kanagawa, Japan
| | - Akio Ohta
- Department of Immunology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
| | - Toshio Miyata
- Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Kiyoshi Ando
- Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan
| | - Takashi Yahata
- Translational Molecular Therapeutics Laboratory, Division of Host Defense Mechanism, Tokai University School of Medicine, Kanagawa, Japan
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Lee JH, Hallis SP, Kwak MK. Continuous TNF-α exposure in mammary epithelial cells promotes cancer phenotype acquisition via EGFR/TNFR2 activation. Arch Pharm Res 2024; 47:465-480. [PMID: 38734854 DOI: 10.1007/s12272-024-01497-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 04/23/2024] [Indexed: 05/13/2024]
Abstract
Tumor necrosis factor alpha (TNF-α), an abundant inflammatory cytokine in the tumor microenvironment (TME), is linked to breast cancer growth and metastasis. In this study, we established MCF10A cell lines incubated with TNF-α to investigate the effects of continuous TNF-α exposure on the phenotypic change of normal mammary epithelial cells. The established MCF10A-LE cell line, through long-term exposure to TNF-α, displayed cancer-like features, including increased proliferation, migration, and sustained survival signaling even in the absence of TNF-α stimulation. Unlike the short-term exposed cell line MCF10A-SE, MCF10A-LE exhibited elevated levels of epidermal growth factor receptor (EGFR) and subsequent TNF receptor 2 (TNFR2), and silencing of EGFR or TNFR2 suppressed the cancer-like phenotype of MCF10A-LE. Notably, we demonstrated that the elevated levels of NAD(P)H oxidase 4 (NOX4) and the resulting increase in reactive oxygen species (ROS) were associated with EGFR/TNFR2 elevation in MCF10A-LE. Furthermore, mammosphere-forming capacity and the expression of cancer stem cell (CSC) markers increased in MCF10A-LE. Silencing of EGFR reversed these effects, indicating the acquisition of CSC-like properties via EGFR signaling. In conclusion, our results reveal that continuous TNF-α exposure activates the EGFR/TNFR2 signaling pathway via the NOX4/ROS axis, promoting neoplastic changes in mammary epithelial cells within the inflammatory TME.
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Affiliation(s)
- Jin-Hee Lee
- Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea
| | - Steffanus Pranoto Hallis
- Department of Pharmacy and BK21FOUR Advanced Program for SmartPharma Leaders, Graduate School of The Catholic University of Korea, Bucheon, Gyeonggi-do, 14662, Republic of Korea
| | - Mi-Kyoung Kwak
- Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea.
- Department of Pharmacy and BK21FOUR Advanced Program for SmartPharma Leaders, Graduate School of The Catholic University of Korea, Bucheon, Gyeonggi-do, 14662, Republic of Korea.
- College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Bucheon, Gyeonggi-do, 14662, Republic of Korea.
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Guo W, Peng D, Liao Y, Lou L, Guo M, Li C, Yu W, Tian X, Wang G, Lv P, Zuo J, Shen H, Li Y. Upregulation of HLA-II related to LAG-3 +CD4 + T cell infiltration is associated with patient outcome in human glioblastoma. Cancer Sci 2024; 115:1388-1404. [PMID: 38480275 PMCID: PMC11093187 DOI: 10.1111/cas.16128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 02/01/2024] [Accepted: 02/17/2024] [Indexed: 05/15/2024] Open
Abstract
Glioblastoma (GBM) is the most common malignant diffuse glioma of the brain. Although immunotherapy with immune checkpoint inhibitors (ICIs), such as programmed cell death protein (PD)-1/PD ligand-1 inhibitors, has revolutionized the treatment of several cancers, the clinical benefit in GBM patients has been limited. Lymphocyte-activation gene 3 (LAG-3) binding to human leukocyte antigen-II (HLA-II) plays an essential role in triggering CD4+ T cell exhaustion and could interfere with the efficiency of anti-PD-1 treatment; however, the value of LAG-3-HLA-II interactions in ICI immunotherapy for GBM patients has not yet been analyzed. Therefore, we aimed to investigate the expression and regulation of HLA-II in human GBM samples and the correlation with LAG-3+CD4+ T cell infiltration. Human leukocyte antigen-II was highly expressed in GBM and correlated with increased LAG-3+CD4+ T cell infiltration in the stroma. Additionally, HLA-IIHighLAG-3High was associated with worse patient survival. Increased interleukin-10 (IL-10) expression was observed in GBM, which was correlated with high levels of HLA-II and LAG-3+ T cell infiltration in stroma. HLA-IIHighIL-10High GBM associated with LAG-3+ T cells infiltration synergistically showed shorter overall survival in patients. Combined anti-LAG-3 and anti-IL-10 treatment inhibited tumor growth in a mouse brain GL261 tumor model. In vitro, CD68+ macrophages upregulated HLA-II expression in GBM cells through tumor necrosis factor-α (TNF-α). Blocking TNF-α-dependent inflammation inhibited tumor growth in a mouse GBM model. In summary, T cell-tumor cell interactions, such as LAG-3-HLA-II, could confer an immunosuppressive environment in human GBM, leading to poor prognosis in patients. Therefore, targeting the LAG-3-HLA-II interaction could be beneficial in ICI immunotherapy to improve the clinical outcome of GBM patients.
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Affiliation(s)
- Wenli Guo
- Department of PathologyThe Second Hospital, Hebei Medical UniversityShijiazhuangChina
- Laboratory of PathologyHebei Medical UniversityShijiazhuangChina
| | - Daijun Peng
- Department of PathologyThe Second Hospital, Hebei Medical UniversityShijiazhuangChina
| | - Yuee Liao
- Department of PathologyThe Second Hospital, Hebei Medical UniversityShijiazhuangChina
| | - Lei Lou
- Department of PathologyThe Second Hospital, Hebei Medical UniversityShijiazhuangChina
| | - Moran Guo
- Department of NeurologySecond Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Chen Li
- Department of NeurosurgerySecond Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Wangyang Yu
- Department of NeurosurgerySecond Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Xiaoxi Tian
- Department of PathologyThe Second Hospital, Hebei Medical UniversityShijiazhuangChina
| | - Guohui Wang
- Department of PathologyThe Second Hospital, Hebei Medical UniversityShijiazhuangChina
| | - Ping Lv
- Department of PharmacologyHebei Medical UniversityShijiazhuangChina
| | - Jing Zuo
- Department of OncologyThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Haitao Shen
- Laboratory of PathologyHebei Medical UniversityShijiazhuangChina
- Hebei Collaborative Innovation Center of Tumor Microecological Metabolism RegulationHebei UniversityBaodingChina
| | - Yuehong Li
- Department of PathologyThe Second Hospital, Hebei Medical UniversityShijiazhuangChina
- Laboratory of PathologyHebei Medical UniversityShijiazhuangChina
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Wang MJ, Xia Y, Gao QL. DNA Damage-driven Inflammatory Cytokines: Reprogramming of Tumor Immune Microenvironment and Application of Oncotherapy. Curr Med Sci 2024; 44:261-272. [PMID: 38561595 DOI: 10.1007/s11596-024-2859-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/29/2024] [Indexed: 04/04/2024]
Abstract
DNA damage occurs across tumorigenesis and tumor development. Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment (TIME) and dominate tumor progression. Accumulating evidence documents that multiple signaling pathways, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein (ATM/ATR), are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines. These cytokines possess multifaced functions in the anti-tumor immune response. Thus, it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines, critical for the development of effective tumor therapies. This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines. We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.
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Affiliation(s)
- Meng-Jie Wang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yu Xia
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Qing-Lei Gao
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Suijkerbuijk KPM, van Eijs MJM, van Wijk F, Eggermont AMM. Clinical and translational attributes of immune-related adverse events. NATURE CANCER 2024; 5:557-571. [PMID: 38360861 DOI: 10.1038/s43018-024-00730-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 01/12/2024] [Indexed: 02/17/2024]
Abstract
With immune checkpoint inhibitors (ICIs) becoming the mainstay of treatment for many cancers, managing their immune-related adverse events (irAEs) has become an important part of oncological care. This Review covers the clinical presentation of irAEs and crucial aspects of reversibility, fatality and long-term sequelae, with special attention to irAEs in specific patient populations, such as those with autoimmune diseases. In addition, the genetic basis of irAEs, along with cellular and humoral responses to ICI therapy, are discussed. Detrimental effects of empirically used high-dose steroids and second-line immunosuppression, including impaired ICI effectiveness, call for more tailored irAE-treatment strategies. We discuss open therapeutic challenges and propose potential avenues to accelerate personalized management strategies and optimize outcomes.
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Affiliation(s)
- Karijn P M Suijkerbuijk
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
| | - Mick J M van Eijs
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Femke van Wijk
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Alexander M M Eggermont
- University Medical Center Utrecht and Princess Máxima Center, Utrecht, the Netherlands
- Comprehensive Cancer Center Munich of the Technical University of Munich and the Ludwig Maximilian University, Munich, Germany
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Pandey S, Anang V, Schumacher MM. Mitochondria driven innate immune signaling and inflammation in cancer growth, immune evasion, and therapeutic resistance. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 386:223-247. [PMID: 38782500 DOI: 10.1016/bs.ircmb.2024.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Mitochondria play an important and multifaceted role in cellular function, catering to the cell's energy and biosynthetic requirements. They modulate apoptosis while responding to diverse extracellular and intracellular stresses including reactive oxygen species (ROS), nutrient and oxygen scarcity, endoplasmic reticulum stress, and signaling via surface death receptors. Integral components of mitochondria, such as mitochondrial DNA (mtDNA), mitochondrial RNA (mtRNA), Adenosine triphosphate (ATP), cardiolipin, and formyl peptides serve as major damage-associated molecular patterns (DAMPs). These molecules activate multiple innate immune pathways both in the cytosol [such as Retionoic Acid-Inducible Gene-1 (RIG-1) and Cyclic GMP-AMP Synthase (cGAS)] and on the cell surface [including Toll-like receptors (TLRs)]. This activation cascade leads to the release of various cytokines, chemokines, interferons, and other inflammatory molecules and oxidative species. The innate immune pathways further induce chronic inflammation in the tumor microenvironment which either promotes survival and proliferation or promotes epithelial to mesenchymal transition (EMT), metastasis and therapeutic resistance in the cancer cell's. Chronic activation of innate inflammatory pathways in tumors also drives immunosuppressive checkpoint expression in the cancer cells and boosts the influx of immune-suppressive populations like Myeloid-Derived Suppressor Cells (MDSCs) and Regulatory T cells (Tregs) in cancer. Thus, sensing of cellular stress by the mitochondria may lead to enhanced tumor growth. In addition to that, the tumor microenvironment also becomes a source of immunosuppressive cytokines. These cytokines exert a debilitating effect on the functioning of immune effector cells, and thus foster immune tolerance and facilitate immune evasion. Here we describe how alteration of the mitochondrial homeostasis and cellular stress drives innate inflammatory pathways in the tumor microenvironment.
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Affiliation(s)
- Sanjay Pandey
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, United States.
| | - Vandana Anang
- International Center for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | - Michelle M Schumacher
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, United States; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States
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McKenzie J, Sneath E, Trinh A, Nolan M, Spain L. Updates in the pathogenesis and management of immune-related enterocolitis, hepatitis and cardiovascular toxicities. IMMUNO-ONCOLOGY TECHNOLOGY 2024; 21:100704. [PMID: 38357008 PMCID: PMC10865026 DOI: 10.1016/j.iotech.2024.100704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment for many solid organ malignancies. Alongside increasing use, the occurrence of immune-related adverse events (irAEs) has also increased and remains a significant challenge when treating patients with ICI. The underlying pathophysiology of irAE development for many organ systems is yet to be elucidated, but may involve unmasking of latent autoimmunity, increased T-cell recognition of shared antigens on cancer and normal tissue and ICI-triggered immune dysregulation with overactivation of proinflammatory pathways and suppression of immune control pathways. Management strategies for irAEs have historically been borrowed from paradigms for conventional autoimmune conditions such as inflammatory bowel disease and autoimmune hepatitis; however, recent translational efforts have clearly demonstrated key differences in underlying immune signalling pathways. As we begin to understand these differences, we must adapt a more targeted approach to immunosuppression and exercise a more nuanced approach with the multiple biologic agents available to mitigate ICI-related toxicity without reversing the antitumour effect of ICI. In this review, we focus on three key immune-related toxicities where recent clinical and translational work has provided nuanced insights into pathogenesis and treatment strategies: enterocolitis, hepatitis and cardiovascular toxicity including myocarditis.
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Affiliation(s)
- J. McKenzie
- Department of Medical Oncology, Melbourne, Australia
| | - E. Sneath
- Department of Medical Oncology, Melbourne, Australia
| | - A. Trinh
- Department of Gastroenterology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Gastroenterology, Royal Melbourne Hospital, Melbourne, Australia
| | - M. Nolan
- Department of Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - L. Spain
- Department of Medical Oncology, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia
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Kong Y, Wang X, Qie R. Immunotherapy-associated cardiovascular toxicities: insights from preclinical and clinical studies. Front Oncol 2024; 14:1347140. [PMID: 38482205 PMCID: PMC10932998 DOI: 10.3389/fonc.2024.1347140] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/12/2024] [Indexed: 11/02/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) have become a widely accepted and effective treatment for various types of solid tumors. Recent studies suggest that cardiovascular immune-related adverse events (irAEs) specifically have an incidence rate ranging from 1.14% to more than 5%. Myocarditis is the most common observed cardiovascular irAE. Others include arrhythmias, pericardial diseases, vasculitis, and a condition resembling takotsubo cardiomyopathy. Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway, cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway, and the recently discovered lymphocyte-activation gene 3 (LAG-3) pathway, play a critical role in boosting the body's natural immune response against cancer cells. While ICIs offer significant benefits in terms of augmenting immune function, they can also give rise to unwanted inflammatory side effects known as irAEs. The occurrence of irAEs can vary in severity, ranging from mild to severe, and can impact the overall clinical efficacy of these agents. This review aims to summarize the underlying mechanisms of cardiovascular irAE from both preclinical and clinical studies for a better understanding of cardiovascular irAE in clinical application.
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Affiliation(s)
- Youqian Kong
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xiaoyu Wang
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Rui Qie
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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Piras L, Zuccanti M, Russo P, Riccio F, Agresti A, Lustri C, Dardani D, Ferrera A, Fiorentini V, Tocci G, Tini Melato G, Volpe M, Barbato E, Battistoni A. Association between Immune Checkpoint Inhibitors and Atherosclerotic Cardiovascular Disease Risk: Another Brick in the Wall. Int J Mol Sci 2024; 25:2502. [PMID: 38473748 PMCID: PMC10931678 DOI: 10.3390/ijms25052502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/11/2024] [Accepted: 02/15/2024] [Indexed: 03/14/2024] Open
Abstract
In recent years, immune checkpoint inhibitors have significantly changed the field of oncology, emerging as first-line treatment, either alone or in combination with other regimens, for numerous malignancies, improving overall survival and progression-free survival in these patients. However, immune checkpoint inhibitors might also cause severe or fatal immune-related adverse events, including adverse cardiovascular events. Initially, myocarditis was recognized as the main immune checkpoint inhibitor-related cardiac event, but our knowledge of other potential immune-related cardiovascular adverse events continues to broaden. Recently, preclinical and clinical data seem to support an association between immune checkpoint inhibitors and accelerated atherosclerosis as well as atherosclerotic cardiovascular events such as cardiac ischemic disease, stroke, and peripheral artery disease. In this review, by offering a comprehensive overview of the pivotal role of inflammation in atherosclerosis, we focus on the potential molecular pathways underlying the effects of immune checkpoint inhibitors on cardiovascular diseases. Moreover, we provide an overview of therapeutic strategies for cancer patients undergoing immunotherapy to prevent the development of cardiovascular diseases.
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Affiliation(s)
- Linda Piras
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Michela Zuccanti
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Paola Russo
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Francesca Riccio
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Antonio Agresti
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Camilla Lustri
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Domenico Dardani
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Armando Ferrera
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Vincenzo Fiorentini
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Giuliano Tocci
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Giacomo Tini Melato
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Massimo Volpe
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
- IRCCS San Raffaele, 00166 Rome, Italy
| | - Emanuele Barbato
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Allegra Battistoni
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
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Kelly AG, Wang W, Rothenberger E, Yang J, Gilligan MM, Kipper FC, Attaya A, Gartung A, Hwang SH, Gillespie MJ, Bayer RL, Quinlivan KM, Torres KL, Huang S, Mitsiades N, Yang H, Hammock BD, Panigrahy D. Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase. Proc Natl Acad Sci U S A 2024; 121:e2314085121. [PMID: 38330013 PMCID: PMC10873624 DOI: 10.1073/pnas.2314085121] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 12/22/2023] [Indexed: 02/10/2024] Open
Abstract
Cancer therapy, including immunotherapy, is inherently limited by chronic inflammation-induced tumorigenesis and toxicity within the tumor microenvironment. Thus, stimulating the resolution of inflammation may enhance immunotherapy and improve the toxicity of immune checkpoint inhibition (ICI). As epoxy-fatty acids (EpFAs) are degraded by the enzyme soluble epoxide hydrolase (sEH), the inhibition of sEH increases endogenous EpFA levels to promote the resolution of cancer-associated inflammation. Here, we demonstrate that systemic treatment with ICI induces sEH expression in multiple murine cancer models. Dietary omega-3 polyunsaturated fatty acid supplementation and pharmacologic sEH inhibition, both alone and in combination, significantly enhance anti-tumor activity of ICI in these models. Notably, pharmacological abrogation of the sEH pathway alone or in combination with ICI counter-regulates an ICI-induced pro-inflammatory and pro-tumorigenic cytokine storm. Thus, modulating endogenous EpFA levels through dietary supplementation or sEH inhibition may represent a unique strategy to enhance the anti-tumor activity of paradigm cancer therapies.
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Affiliation(s)
- Abigail G. Kelly
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
| | - Weicang Wang
- Department of Entomology and Nematology, University of California, Davis,CA95616
- University of California Davis Comprehensive Cancer Center, Sacramento, CA95817
- Department of Food Science, Purdue University, West Lafayette, IN47907
| | - Eva Rothenberger
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
| | - Jun Yang
- Department of Entomology and Nematology, University of California, Davis,CA95616
- University of California Davis Comprehensive Cancer Center, Sacramento, CA95817
| | - Molly M. Gilligan
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
| | - Franciele C. Kipper
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
| | - Ahmed Attaya
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
| | - Allison Gartung
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
| | - Sung Hee Hwang
- Department of Entomology and Nematology, University of California, Davis,CA95616
- University of California Davis Comprehensive Cancer Center, Sacramento, CA95817
| | - Michael J. Gillespie
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
| | - Rachel L. Bayer
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
| | - Katherine M. Quinlivan
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
| | - Kimberly L. Torres
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
| | - Sui Huang
- Institute of Systems Biology, Seattle, WA98109
| | - Nicholas Mitsiades
- University of California Davis Comprehensive Cancer Center, Sacramento, CA95817
- Department of Internal Medicine, University of CaliforniaDavis,CA95817
| | - Haixia Yang
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Food Nutrition and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing100083, China
| | - Bruce D. Hammock
- Department of Entomology and Nematology, University of California, Davis,CA95616
- University of California Davis Comprehensive Cancer Center, Sacramento, CA95817
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA02215
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Ali LR, Lenehan PJ, Cardot-Ruffino V, Dias Costa A, Katz MH, Bauer TW, Nowak JA, Wolpin BM, Abrams TA, Patel A, Clancy TE, Wang J, Mancias JD, Reilley MJ, Stucky CCH, Bekaii-Saab TS, Elias R, Merchant N, Slingluff CL, Rahma OE, Dougan SK. PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer. Clin Cancer Res 2024; 30:542-553. [PMID: 37733830 PMCID: PMC10831338 DOI: 10.1158/1078-0432.ccr-23-1444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/28/2023] [Accepted: 09/19/2023] [Indexed: 09/23/2023]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease in which bulky tumor burden and limited time to develop antitumor T cells may have contributed to poor clinical efficacy. Here, we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti-PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors. EXPERIMENTAL DESIGN We used single-cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor. RESULTS PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T-cell clonotypes observed in the tumor. CONCLUSIONS Cytotoxic T cells in the blood of patients with PDAC remain sensitive to reinvigoration by PD-1 blockade, and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti-PD-1 reinvigoration and marks these T cells as non-productive contributors to antitumor immunity. See related commentary by Lander and DeNardo, p. 474.
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Affiliation(s)
- Lestat R. Ali
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Immunology, Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Patrick J. Lenehan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Immunology, Harvard Medical School, Boston, Massachusetts
| | - Victoire Cardot-Ruffino
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Immunology, Harvard Medical School, Boston, Massachusetts
| | - Andressa Dias Costa
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Matthew H.G. Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Todd W. Bauer
- Department of Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Jonathan A. Nowak
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Brian M. Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Thomas A. Abrams
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Anuj Patel
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Thomas E. Clancy
- Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jiping Wang
- Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Joseph D. Mancias
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Matthew J. Reilley
- Division of Hematology and Oncology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
| | | | | | - Rawad Elias
- Hartford Healthcare Cancer Institute, Hartford, Connecticut
| | - Nipun Merchant
- Department of Surgery, University of Miami, Miami, Florida
| | - Craig L. Slingluff
- Department of Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Osama E. Rahma
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Stephanie K. Dougan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Immunology, Harvard Medical School, Boston, Massachusetts
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Alim LF, Keane C, Souza-Fonseca-Guimaraes F. Molecular mechanisms of tumour necrosis factor signalling via TNF receptor 1 and TNF receptor 2 in the tumour microenvironment. Curr Opin Immunol 2024; 86:102409. [PMID: 38154421 DOI: 10.1016/j.coi.2023.102409] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 11/27/2023] [Accepted: 11/30/2023] [Indexed: 12/30/2023]
Abstract
Tumour necrosis factor (TNF) is a primary mediator of inflammatory processes by facilitating cell death, immune cell activation and triggering of inflammation. In the cancer context, research has revealed TNF as a multifaceted cytokine that can be both pro- or anti-tumorigenic depending on what context is observed. We explore the plethora of ways that TNF and its receptors manipulate the functional and phenotypic characteristics in the tumour microenvironment (TME) on both tumour cells and immune cells, promoting either tumour elimination or progression. Here, we discuss the latest cutting-edge TNF-focused biologics currently in clinical translation that modifies the TME to derive greater immune responses and therapeutic outcomes, and further give perspectives on the future of targeting TNF in the context of cancer by emerging technological approaches.
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Affiliation(s)
- Louisa F Alim
- Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
| | - Colm Keane
- Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia; Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia
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Qin G, Bai F, Hu H, Zhang J, Zhan W, Wu Z, Li J, Fu Y, Deng Y. Targeting the NAT10/NPM1 axis abrogates PD-L1 expression and improves the response to immune checkpoint blockade therapy. Mol Med 2024; 30:13. [PMID: 38243170 PMCID: PMC10799409 DOI: 10.1186/s10020-024-00780-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 01/05/2024] [Indexed: 01/21/2024] Open
Abstract
BACKGROUND PD-1/PD-L1 play a crucial role as immune checkpoint inhibitors in various types of cancer. Although our previous study revealed that NPM1 was a novel transcriptional regulator of PD-L1 and stimulated the transcription of PD-L1, the underlying regulatory mechanism remains incompletely characterized. METHODS Various human cancer cell lines were used to validate the role of NPM1 in regulating the transcription of PD-L1. The acetyltransferase NAT10 was identified as a facilitator of NPM1 acetylation by coimmunoprecipitation and mass spectrometry. The potential application of combined NAT10 inhibitor and anti-CTLA4 treatment was evaluated by an animal model. RESULTS We demonstrated that NPM1 enhanced the transcription of PD-L1 in various types of cancer, and the acetylation of NPM1 played a vital role in this process. In particular, NAT10 facilitated the acetylation of NPM1, leading to enhanced transcription and increased expression of PD-L1. Moreover, our findings demonstrated that Remodelin, a compound that inhibits NAT10, effectively reduced NPM1 acetylation, leading to a subsequent decrease in PD-L1 expression. In vivo experiments indicated that Remodelin combined with anti-CTLA-4 therapy had a superior therapeutic effect compared with either treatment alone. Ultimately, we verified that the expression of NAT10 exhibited a positive correlation with the expression of PD-L1 in various types of tumors, serving as an indicator of unfavorable prognosis. CONCLUSION This study suggests that the NAT10/NPM1 axis is a promising therapeutic target in malignant tumors.
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Affiliation(s)
- Ge Qin
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
| | - Fan Bai
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
| | - Huabin Hu
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
| | - Jianwei Zhang
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
| | - Weixiang Zhan
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
| | - Zehua Wu
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
| | - Jianxia Li
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
| | - Yang Fu
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China
| | - Yanhong Deng
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China.
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China.
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Yuan Cun Er Rd No. 26, Guangzhou, 510655, People's Republic of China.
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Li YR, Lyu Z, Tian Y, Fang Y, Zhu Y, Chen Y, Yang L. Advancements in CRISPR screens for the development of cancer immunotherapy strategies. Mol Ther Oncolytics 2023; 31:100733. [PMID: 37876793 PMCID: PMC10591018 DOI: 10.1016/j.omto.2023.100733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2023] Open
Abstract
CRISPR screen technology enables systematic and scalable interrogation of gene function by using the CRISPR-Cas9 system to perturb gene expression. In the field of cancer immunotherapy, this technology has empowered the discovery of genes, biomarkers, and pathways that regulate tumor development and progression, immune reactivity, and the effectiveness of immunotherapeutic interventions. By conducting large-scale genetic screens, researchers have successfully identified novel targets to impede tumor growth, enhance anti-tumor immune responses, and surmount immunosuppression within the tumor microenvironment (TME). Here, we present an overview of CRISPR screens conducted in tumor cells for the purpose of identifying novel therapeutic targets. We also explore the application of CRISPR screens in immune cells to propel the advancement of cell-based therapies, encompassing T cells, natural killer cells, dendritic cells, and macrophages. Furthermore, we outline the crucial components necessary for the successful implementation of immune-specific CRISPR screens and explore potential directions for future research.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Zibai Lyu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Yanxin Tian
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Ying Fang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Yichen Zhu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Yuning Chen
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Lili Yang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
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