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Lakhotia R, Melani C, Dunleavy K, Pittaluga S, Desai S, Ahlman MA, Lucas N, Steinberg SM, Jaffe ES, Wilson WH, Roschewski M. Phase 2 study of alemtuzumab and dose-adjusted EPOCH-R in relapsed or refractory aggressive B-cell lymphomas. Leuk Lymphoma 2025; 66:1088-1099. [PMID: 39899393 DOI: 10.1080/10428194.2025.2457553] [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: 10/25/2024] [Revised: 01/12/2025] [Accepted: 01/18/2025] [Indexed: 02/05/2025]
Abstract
Immune cells within the lymphoma tumor microenvironment promote immune evasion and are rational therapeutic targets. Alemtuzumab targets CD52 expressed on malignant B-cells and infiltrating nonmalignant T-cells. We evaluated the safety and efficacy of alemtuzumab with DA-EPOCH-R in 48 patients with relapsed/refractory aggressive B-cell lymphoma. Febrile neutropenia occurred in 18% of cycles and serious infections in 21% of patients. Responses were observed in 30 (62%) patients, including 12 (80%) patients with classical HL and 3 (75%) patients with T-cell/histiocyte-rich large B-cell lymphoma (THRLCL). Seventeen (35%) patients achieved complete responses, and 12 (25%) were bridged to consolidation. The 2-year progression-free survival (PFS) and overall survival were 22.1% (95% CI, 11.5-34.7%) and 45.2% (95% CI, 34.3-58.9%), respectively. The 2-year PFS for HL and THRLCL patients was 35% and 50%, respectively. Alemtuzumab can be safely combined with DA-EPOCH-R in relapsed/refractory aggressive B-cell lymphomas and can induce durable responses in patients with T-cell-rich microenvironments.
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Affiliation(s)
- Rahul Lakhotia
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Christopher Melani
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Kieron Dunleavy
- Hematology, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA
| | - Stefania Pittaluga
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sanjal Desai
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA
| | - Mark A Ahlman
- Radiology and Imaging, Medical College of Georgia, Augusta, GA, USA
| | - Nicole Lucas
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Seth M Steinberg
- Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Elaine S Jaffe
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Wyndham H Wilson
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Mark Roschewski
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Güven DC, Thong MS, Arndt V. Survivorship outcomes in patients treated with immune checkpoint inhibitors: a scoping review. J Cancer Surviv 2025; 19:806-845. [PMID: 38175366 PMCID: PMC12081552 DOI: 10.1007/s11764-023-01507-w] [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: 09/15/2023] [Accepted: 11/26/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have become a central part of cancer care. However, the survivorship outcomes in patients treated with ICIs are understudied. Therefore, we conducted a scoping review to evaluate the current status of the field and to establish research gaps regarding survivorship outcomes with ICIs in real-life cohorts. METHODS We used the Web of Science, PubMed, and Embase databases to systematically filter published studies with real-life cohorts from January 1, 2010, until October 19, 2022. Studies evaluating at least one survivorship outcome in ICI-treated patients were included. RESULTS A total of 39 papers were included. Quality of life (QoL) (n = 23), toxicity burden (n = 16), and psychosocial issues (n = 9) were the most frequently evaluated survivorship outcomes. Anti-PD-1/PD-L1 monotherapy and a response to treatment were associated with better QoL. In addition, the ICIs were associated with grade 3 or higher immune-related adverse events (irAEs) in 10-15% and late/long-term irAEs in 20-30% of the survivors. Regarding psychosocial problems, over 30% of survivors showed evidence of anxiety and depression, and 30-40% of survivors reported neurocognitive impairments. CONCLUSION The survivors treated with ICIs have impairments in most survivorship domains. Further research is needed to gather data on the understudied survivorship outcomes like late and long-term effects, fertility, financial toxicity, and return to work in survivors treated with ICIs. IMPLICATIONS FOR CANCER SURVIVORS Available evidence demonstrates that a significant portion of survivors treated with ICIs have a significant toxicity burden, lower QoL than the general population, and a high rate of psychosocial problems.
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Affiliation(s)
- Deniz Can Güven
- Department of Medical Oncology, Hacettepe University Cancer Institute, 06100 Sihhiye, Ankara, Turkey.
- Health Sciences University, Elazig City Hospital, Elazig, Turkey.
- Unit of Cancer Survivorship, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Melissa Sy Thong
- Unit of Cancer Survivorship, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Volker Arndt
- Unit of Cancer Survivorship, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
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3
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Tumuluru S, Godfrey JK, Cooper A, Yu J, Chen X, MacNabb BW, Venkataraman G, Zha Y, Pelzer B, Song J, Duns G, Sworder BJ, Raj S, Bolen C, Penuel E, Postovalova E, Kotlov N, Bagaev A, Fowler N, Shouval R, Smith SM, Alizadeh AA, Steidl C, Kline J. Integrative genomic analysis of DLBCL identifies immune environments associated with bispecific antibody response. Blood 2025; 145:2460-2472. [PMID: 39869833 DOI: 10.1182/blood.2024025355] [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: 05/21/2024] [Revised: 01/10/2025] [Accepted: 01/11/2025] [Indexed: 01/29/2025] Open
Abstract
ABSTRACT Most patients with diffuse large B-cell lymphoma (DLBCL) treated with immunotherapies such as bispecific antibodies (BsAbs) or chimeric antigen receptor (CAR) T cells fail to achieve durable treatment responses, underscoring the need for a deeper understanding of mechanisms that regulate the immune environment and response to treatment. Here, an integrative multiomics approach was applied to multiple large independent data sets to characterize DLBCL immune environments and to define their association with tumor cell-intrinsic genomic alterations and outcomes to CD19-directed CAR T-cell and CD20 × CD3 BsAb therapies. This approach effectively segregated DLBCLs into 4 immune quadrants (IQs) defined by cell-of-origin and immune-related gene set expression scores. These quadrants consisted of activated B cell-like (ABC) hot, ABC cold, germinal center B cell-like (GCB) hot, and GCB cold DLBCLs. Recurrent genomic alterations were enriched in each IQ, suggesting that lymphoma cell-intrinsic alterations contribute significantly to orchestrating unique DLBCL immune environments. For instance, SOCS1 loss-of-function mutations were significantly enriched among GCB hot DLBCLs, identifying a putative subset of inflamed DLBCLs that may be inherently susceptible to immunotherapy. In patients with relapsed/refractory DLBCL, DLBCL-IQ assignment correlated significantly with clinical benefit with a CD20 × CD3 BsAb (N = 74), but not with CD19-directed CAR T cells (Stanford, N = 51; Memorial Sloan Kettering Cancer Center, N = 69). Thus, DLBCL-IQ provides a new framework to conceptualize the DLBCL immune landscape and suggests the endogenous immune environment has a more significant impact on outcomes to BsAb than CAR T-cell treatment.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/pathology
- Antibodies, Bispecific/therapeutic use
- Antibodies, Bispecific/immunology
- Tumor Microenvironment/immunology
- Tumor Microenvironment/genetics
- Genomics/methods
- Antigens, CD19/immunology
- Immunotherapy, Adoptive
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Affiliation(s)
- Sravya Tumuluru
- Biological Sciences Division, Committee on Cancer Biology, The University of Chicago, Chicago, IL
| | - James K Godfrey
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA
| | - Alan Cooper
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
| | - Jovian Yu
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
| | - Xiufen Chen
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
| | - Brendan W MacNabb
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA
| | | | - Yuanyuan Zha
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
| | - Benedikt Pelzer
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Joo Song
- Department of Pathology, City of Hope, Duarte, CA
| | - Gerben Duns
- Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
| | - Brian J Sworder
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA
| | - Sandeep Raj
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | | | | | | | | | - Roni Shouval
- Department of Medicine, Weill Cornell Medical College, New York, NY
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sonali M Smith
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
| | - Ash A Alizadeh
- Division of Oncology, Department of Medicine, Stanford University, Palo Alto, CA
| | - Christian Steidl
- Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada
| | - Justin Kline
- Biological Sciences Division, Committee on Cancer Biology, The University of Chicago, Chicago, IL
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
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4
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Stewart J, Damania B. Innate Immune Recognition of EBV. Curr Top Microbiol Immunol 2025. [PMID: 40399572 DOI: 10.1007/82_2025_297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025]
Abstract
Epstein-Barr virus (EBV) is a very successful human pathogen, with ~95% seroprevalence worldwide (Mentzer et al, Nat Commun 13:1818, 2022). If contracted in early childhood, EBV infection is typically asymptomatic; however, infections in adolescence and adulthood can manifest as infectious mononucleosis (IM). The innate immune response is the first line of defense, and its function is critical for controlling EBV infection. During EBV infection, components of the virus, known as pathogen-associated molecular patterns (PAMPs), are recognized by germline-encoded pattern recognition receptors (PRRs). PRRs are found on both non-immune and immune cells including antigen-presenting cells, such as macrophages, monocytes, dendritic cells, natural killer (NK), and mast cells. PRRs are also found on B cells and epithelial cells, the primary targets of EBV infection. Without immune surveillance, EBV can transform cells inducing various malignancies. Conversely, a prolonged innate immune response can lead to chronic inflammation which increases the likelihood of cancer. This review discusses innate immune recognition of EBV and its associated diseases.
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Affiliation(s)
- Jessica Stewart
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Srinivasan S, Narayan A, Dhamne C, Chichra A, Khemani P, Dhariwal N, Ranjan R, Shah S, Shet T, Gollamudi VRM, Roy Moulik N, Banavali SD, Narula G. Combination of fixed low-dose nivolumab and bendamustine in children with high-risk relapsed/refractory classical Hodgkin lymphoma. Br J Haematol 2025. [PMID: 40394816 DOI: 10.1111/bjh.20148] [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: 01/28/2025] [Accepted: 05/01/2025] [Indexed: 05/22/2025]
Abstract
A retrospective study of 18 pediatric patients with high-risk relapsed/refractory classical Hodgkin lymphoma demonstrated that a fixed low-dose combination of nivolumab and bendamustine achieved an 88% complete response rate, with 1-year progression-free survival (PFS) of 88.2% and overall survival (OS) of 94.4%.
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Affiliation(s)
- Shyam Srinivasan
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Aditya Narayan
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Chetan Dhamne
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Akanksha Chichra
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Poonam Khemani
- Homi Bhabha National Institute, Mumbai, India
- Department of Paediatric Oncology, Homi Bhabha Cancer Hospital (HBCH), Varanasi, India
| | - Nidhi Dhariwal
- Homi Bhabha National Institute, Mumbai, India
- Department of Paediatric Oncology, Homi Bhabha Cancer Hospital and Research Centre (HBCHRC), Mullanpur, India
| | - Raghwesh Ranjan
- Homi Bhabha National Institute, Mumbai, India
- Department of Paediatric Oncology, Homi Bhabha Cancer Hospital (HBCH), Varanasi, India
| | - Sneha Shah
- Homi Bhabha National Institute, Mumbai, India
- Department of Nuclear Medicine, Tata Memorial Hospital/ACTREC, Mumbai, India
| | - Tanuja Shet
- Homi Bhabha National Institute, Mumbai, India
- Department of Pathology, Tata Memorial Hospital/ACTREC, Mumbai, India
| | - Venkata Rama Mohan Gollamudi
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Nirmalya Roy Moulik
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Shripad D Banavali
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Gaurav Narula
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
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6
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Jia Y, Li J, Mei W, Zhang H, Wang Z, Xie X, Gao C, Xu X, Li F. Pan-HDAC inhibitor LAQ824 inhibits the progression of pancreatic ductal adenocarcinoma and suppresses immune escape by promoting antigen presentation. Int Immunopharmacol 2025; 154:114528. [PMID: 40158429 DOI: 10.1016/j.intimp.2025.114528] [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: 01/26/2025] [Revised: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 04/02/2025]
Abstract
Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide, with a dismal 5-year survival rate. New drugs targeting pancreatic ductal adenocarcinoma (PDAC), the primary pathological subtype, are urgently needed. LAQ824, a novel pan-histone deacetylase inhibitor (HDACi), has shown anti-tumor activity in various cancers, but its effects on PDAC remain unexplored. This study investigates the therapeutic potential of LAQ824 in PDAC and its role in modulating immune escape mechanisms. Using a subcutaneous tumor model in C57BL/6 J mice, LAQ824's anti-tumor effects were evaluated. In vitro and in vivo experiments-including IHC, flow cytometry, RNA sequencing, and single-cell RNA sequencing-demonstrated that LAQ824 inhibits tumor proliferation, suppresses the epithelial-mesenchymal transition (EMT), and induces apoptosis. LAQ824 also enhances immunogenicity by upregulating MHC-I-mediated antigen presentation, increasing immune cell infiltration, and promoting CD8+ T cell maturation and differentiation. Mechanistically, LAQ824 upregulated MHC-I expression by enhancing chromatin accessibility of related genes, with HDAC1 identified as a key repressor of MHC-I in PDAC cells. In conclusion, we found that LAQ824 has a significant anti-tumor effect in PDAC. LAQ824 not only directly affects general biological behaviors such as proliferation, apoptosis, and EMT, but also increases the immunogenicity of tumor cells by upregulating the expression of MHC-I in PDAC, which promotes the antigen presentation process and enhances anti-tumor immunity. By showcasing LAQ824's potential as a therapeutic target against PDAC, the present study provides novel insights into the link between epigenetic regulation and immunogenicity in PDAC.
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Affiliation(s)
- Yuchen Jia
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China
| | - Jie Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China
| | - Wentong Mei
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China; Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Haoyu Zhang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China
| | - Zheng Wang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China
| | - Xiaozhou Xie
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China
| | - Chongchong Gao
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China.
| | - Xiaoqing Xu
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China.
| | - Fei Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China.
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7
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Li BY, Li HL, Zeng FE, Luan XY, Liu BQ, Wang ZZ, Zhang L, Dong XZ. Identification of PD-L1-related biomarkers for selecting gastric adenocarcinoma patients for PD-1/PD-L1 inhibitor therapy. Discov Oncol 2025; 16:689. [PMID: 40338384 PMCID: PMC12061829 DOI: 10.1007/s12672-025-02515-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 04/25/2025] [Indexed: 05/09/2025] Open
Abstract
PD-1/PD-L1 inhibitors have been used to treat gastric cancer, and PD-L1 expression has been identified as a biomarker for predicting the effectiveness of immunotherapy in the treatment of gastric cancer. However, PD-L1 expression prediction for immunotherapy response is inaccurate, and improved response biomarkers are required. Thus, it is important to identify additional biomarkers that can predict the responses to PD-1/PD-L1 monoclonal antibodies in gastric cancer. In this study, GO and KEGG enrichment analysis of 142 DEGs co-expressed with PD-L1 were performed, and 41 genes were identified based on the intersection of the mRNA-significant GO term network and the mRNA-significant signalling pathway network. Further intersection analysis of the 41 candidate genes and 137 positive immunotherapy response genes indicated that BATF2 significantly affects the overall survival of GC patients. The transcription factor prediction for BATF2 identified additional potential predictors and therapeutic targets for GC. STAT and IRF family members were predicted to be transcription factors for BATF2. In addition, BATF2 knockdown significantly promoted GC cell growth, and PD-L1 expression was upregulated in si-BATF2-treated MKN-45 cells. Thus, BATF2 may serve as a biomarker for predicting the efficacy of PD-L1 blockade therapy in GC. BATF2 acts as a tumour suppressor gene during the development of GC. BATF2 is closely related to PD-L1 expression in GC, and high BATF2 expression positively correlates with low PD-L1 expression. BATF2 can be used as a potential biomarker and therapeutic target for responding to anti-PD-1 and anti-PD-L1 immunotherapies in GC.
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Affiliation(s)
- Bo-Ya Li
- Department of Pharmacy, Xuanwu Hospital, Capital Medical University, National Clinical Research Centre for Geriatric Diseases, Beijing, China
| | - Hui-Ling Li
- Department of Pharmacy, Xuanwu Hospital, Capital Medical University, National Clinical Research Centre for Geriatric Diseases, Beijing, China
| | - Fei-Er Zeng
- Department of Genetics and Genome Biology, Leicester Cancer Research Centre, University of Leicester, Leicester, LE2 7LX, UK
| | - Xuan-Yu Luan
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Bi-Qing Liu
- Department of Pharmacy, Children's Hospital Affiliated to Capital Institute of Paediatrics, Beijing, China
| | - Zhi-Zhou Wang
- Department of Pharmacy, Xuanwu Hospital, Capital Medical University, National Clinical Research Centre for Geriatric Diseases, Beijing, China
| | - Lan Zhang
- Department of Pharmacy, Xuanwu Hospital, Capital Medical University, National Clinical Research Centre for Geriatric Diseases, Beijing, China.
| | - Xian-Zhe Dong
- Department of Pharmacy, Xuanwu Hospital, Capital Medical University, National Clinical Research Centre for Geriatric Diseases, Beijing, China.
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8
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Wang Q, Yuan F, Zuo X, Li M. Breakthroughs and challenges of organoid models for assessing cancer immunotherapy: a cutting-edge tool for advancing personalised treatments. Cell Death Discov 2025; 11:222. [PMID: 40335487 PMCID: PMC12059183 DOI: 10.1038/s41420-025-02505-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 04/16/2025] [Accepted: 04/23/2025] [Indexed: 05/09/2025] Open
Abstract
Organoid models are powerful tools for evaluating cancer immunotherapy that provide a more accurate representation of the tumour microenvironment (TME) and immune responses than traditional models. This review focuses on the latest advancements in organoid technologies, including immune cell co-culture, 3D bioprinting, and microfluidic systems, which enhance the modelling of TME and facilitate the assessment of immune therapies such as immune checkpoint inhibitors (ICIs), CAR-T therapies, and oncolytic viruses. Although these models have great potential in personalised cancer treatment, challenges persist in immune cell diversity, long-term culture stability, and reproducibility. Future developments integrating artificial intelligence (AI), multi-omics, and high-throughput platforms are expected to improve the predictive power of organoid models and accelerate the clinical translation of immunotherapy.
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Affiliation(s)
- Qian Wang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210009, Jiangsu, PR China
- The Fourth Clinical College of Nanjing Medical University, Nanjing, 210009, Jiangsu, PR China
| | - Fangwei Yuan
- Department of Thoracic Surgery, Lian Shui County People's Hospital, Huaian, 223400, Jiangsu, PR China
| | - Xianglin Zuo
- Biobank of Jiangsu Cancer Hospital (Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University), Nanjing, 210000, Jiangsu, PR China.
| | - Ming Li
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210009, Jiangsu, PR China.
- The Fourth Clinical College of Nanjing Medical University, Nanjing, 210009, Jiangsu, PR China.
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9
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Zhang ZF, Zhang Y, Chen YW, Cao GS, Zheng XD, Sun R, Peng H, Tian ZG, Sun HY. CD200R blockade enhances anti-tumor immunity by unleashing NK and CD8 + T cells in tumor. Acta Pharmacol Sin 2025:10.1038/s41401-025-01556-0. [PMID: 40329005 DOI: 10.1038/s41401-025-01556-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 03/30/2025] [Indexed: 05/08/2025]
Abstract
Immune checkpoint inhibitors have revolutionized cancer therapy, but a large proportion of patients do not respond well to current checkpoint immunotherapies. CD200R (also known as OX2R) is a transmembrane glycoprotein of the immunoglobulin superfamily that is mainly expressed on myeloid and lymphoid-derived immunocompetent cells such as myeloid cells, natural killer (NK), and CD8+ T cells. In this study, we investigated the therapeutic potential and cellular mechanisms of targeting CD200R in tumor immunotherapy. We established 4 subcutaneous tumor mouse models using MC38 (colon cancer), MCA205 (fibrosarcoma), LLC (lung cancer), and EO771 (mammary cancer) cell lines. We found that CD200R was highly expressed on tumor-infiltrating NK and CD8+ T cells with exhausted phenotypes in the four subcutaneous tumor mouse models. Either genetic ablation or antibody blockade of CD200R retarded tumor growth and prolonged the survival of tumor-bearing mice by preventing or reversing exhaustion of both NK cells and CD8+ T cells. The combined therapy of CD200R antibody with anti-PD-1/anti-PD-L1 synergistically inhibited tumor growth. By depletion of NK or/and CD8+ T cells, we demonstrated that both cell types contributed to the anti-tumor efficacy of CD200R blockade in tumor-bearing mice. Further, the blockade of human CD200R significantly enhanced human NK cell function and inhibited human tumor growth in PBMC-reconstituted xenograft mice. Our results demonstrate that CD200R is a potential immune checkpoint molecule that can suppress the tumoricidal activities of NK and CD8+ T cells, and could thus be exploited as a therapeutic target in the future.
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Affiliation(s)
- Zheng-Feng Zhang
- National Key Laboratory of Immune Response and Immunotherapy, The Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Yu Zhang
- National Key Laboratory of Immune Response and Immunotherapy, The Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Ya-Wen Chen
- National Key Laboratory of Immune Response and Immunotherapy, The Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Guo-Shuai Cao
- Hefei TG ImmunoPharma Corporation Limited, Hefei, 230027, China
| | - Xiao-Dong Zheng
- National Key Laboratory of Immune Response and Immunotherapy, The Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Rui Sun
- National Key Laboratory of Immune Response and Immunotherapy, The Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Hui Peng
- National Key Laboratory of Immune Response and Immunotherapy, The Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Zhi-Gang Tian
- National Key Laboratory of Immune Response and Immunotherapy, The Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
| | - Hao-Yu Sun
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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10
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Xia L, Liu JY, Yu C, Lin HW, Hu YH, Hu GS, He YH, Chen YY, Luo WX, Xia NS, Liu W. PILRα on tumor cells interacts with the T cell surface protein CD99 to suppress antitumor immunity. NATURE CANCER 2025:10.1038/s43018-025-00958-7. [PMID: 40312493 DOI: 10.1038/s43018-025-00958-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 03/24/2025] [Indexed: 05/03/2025]
Abstract
Immune checkpoint blockade using anti-programmed cell death protein 1/programmed cell death 1 ligand 1 antibody effectively targets the tumor-T cell interaction in cancer treatment, yet the overall response rate of less than 30% necessitates the identification of additional immune checkpoints modulating T cell function. Here, we identified the tumor cell-expressed paired immunoglobulin-like type 2 receptor alpha (PILRα) as an immune suppressor targeting T cells using high-throughput screening. PILRα inhibits T cell activation, proliferation and effector function by targeting CD99, a T cell surface antigen, suppressing ZAP70/NFAT/IL-2/JAK/STAT signaling. A cluster of O-glycosylated serine and threonine residues within the stalk region is critical for PILRα-CD99 interactions. Blocking these interactions with a stalk-targeting anti-PILRα antibody enhances T cell antitumor immunity and suppresses tumor growth. When combined with programmed cell death protein 1 antibody, anti-PILRα antibody shows synergistic tumor suppression. Notably, PILRα is highly expressed in several human cancers and predicts poor prognosis. These findings unveil PILRα as an immune checkpoint with therapeutic potential for clinical cancer immunotherapy.
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Affiliation(s)
- Lin Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
- ShenZhen Research Institute, Xiamen University, Shenzhen, China.
| | - Jun-Yi Liu
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen, China
| | - Chao Yu
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen, China
| | - Hong-Wei Lin
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen, China
| | - Ya-Hong Hu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Guo-Sheng Hu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Yao-Hui He
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Yun-Yao Chen
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen, China
| | - Wen-Xin Luo
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen, China.
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China.
| | - Ning-Shao Xia
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen, China.
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China.
| | - Wen Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
- ShenZhen Research Institute, Xiamen University, Shenzhen, China.
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11
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Salem A, Mehdizadeh M, Parkhideh S. Allogenic stem cell transplantation response for relapsed or refractory Hodgkin lymphoma patients: An experience in Iran. Transpl Immunol 2025; 90:102228. [PMID: 40204007 DOI: 10.1016/j.trim.2025.102228] [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: 09/12/2024] [Revised: 03/30/2025] [Accepted: 04/06/2025] [Indexed: 04/11/2025]
Abstract
Stem cell transplantation (SCT) is a potentially curative therapeutic approach for patients diagnosed with high-risk classic Hodgkin Lymphoma (cHL), a rare lymphoproliferative disorder. This study presents a comprehensive retrospective analysis of 273 patients with relapsed or refractory cHL referred to Taleghani Hospital in Tehran, Iran, over a 14-year period (2007-2021). The results indicated that 63 % of individuals receiving autologous-SCT achieved a complete response. However, approximately 4 % of the study population (10 patients) experienced treatment failure after autologous-SCT and proceeded to allogeneic-SCT (Group I). Additionally, in ten other cases, autologous-SCT was not feasible, and treatment was exclusively managed through allogeneic-SCT (Group II). Demographic and clinical characteristics, including gender, cHL subtype, history of radiotherapy, presence of bulky disease, and incidence of graft-versus-host disease (GVHD), were collected and analyzed to assess treatment outcomes. The overall survival (OS) was 42.1 months for Group I and 17.3 months for Group II. Although the overall complete response (CR) for the entire cohort was 45 %, the corresponding CR for Groups I and II were 60 and 30 %, respectively. In conclusion, allogenic-SCT appears to be a viable therapeutic strategy for at least 50 % of patients experiencing autologous-SCT failure. The efficacy of allogenic-SCT may be influenced by factors such as cHL subtype, and prior auto-SCT therapy. Notably, individuals in Group I who experienced graft-versus-host disease (GVHD) exhibited prolonged survival.
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Affiliation(s)
- Amineh Salem
- Department of Medical Oncology and Hematology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mahshid Mehdizadeh
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sayeh Parkhideh
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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Alibrahim MN, Gloghini A, Carbone A. Classic Hodgkin lymphoma: Pathobiological features that impact emerging therapies. Blood Rev 2025; 71:101271. [PMID: 39904647 DOI: 10.1016/j.blre.2025.101271] [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: 11/28/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/06/2025]
Abstract
Classic Hodgkin lymphoma (cHL) is defined by distinctive Hodgkin Reed-Sternberg (HRS) cells, which are CD30+/CD15+ multinucleated tumor cells lacking typical B-cell markers. These cells comprise <5 % of tumor mass but orchestrate an extensive immunosuppressive tumor microenvironment (TME). Classic HL was curable with radiation therapy and multi-agent chemotherapy. Despite high cure rates, treatment-related toxicities remain significant. The goals of multimodality therapy are to achieve a cure while minimizing treatment-associated toxicity. Advances in molecular insights into HRS cells have led to transformative therapies, including checkpoint inhibitors, antibody-drug conjugates like brentuximab vedotin, which have shown remarkable efficacy, especially in relapsed or refractory disease. However, challenges persist due to the heterogeneity of cHL, driven by the complex biology of HRS cells and their surrounding tumor microenvironment. Novel approaches such as single-cell RNA sequencing and circulating tumor DNA profiling provide promising strategies to address these challenges. This review examines the origin, morphology, phenotype, and genetic profiles of HRS cells, highlighting key pathobiological features, including biomarkers and Epstein-Barr Virus involvement. It also explores the biological mechanisms underlying HRS cell survival and evaluates standard and emerging therapies, offering insights into the rationale for novel treatment strategies.
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Affiliation(s)
| | - Annunziata Gloghini
- Department of Avanced Pathology, Fondazione IRCCS, Istituto Nazionale dei Tumori Milano, Italy.
| | - Antonino Carbone
- Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, Aviano, Italy.
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13
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Aoki T, Wierzbicki K, Sun S, Steidl C, Giulino-Roth L. Tumor-microenvironment and molecular biology of classic Hodgkin lymphoma in children, adolescents, and young adults. Front Oncol 2025; 15:1515250. [PMID: 40376590 PMCID: PMC12078164 DOI: 10.3389/fonc.2025.1515250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 03/31/2025] [Indexed: 05/18/2025] Open
Abstract
Classic Hodgkin lymphoma (cHL) exhibits a bimodal age distribution with incidence peaks in adolescents and young adults (AYAs) aged 15-39 years and in older adults over 50 years. The unique biology of cHL, characterized by a tumor microenvironment (TME) composed predominantly of non-malignant immune and stromal cells, plays a pivotal role in supporting Hodgkin and Reed-Sternberg (HRS) cells, the malignant cells of cHL. Understanding the role of the TME in cHL and its age-related differences is crucial for deciphering differential disease etiologies and developing biomarker-driven targeted therapies. Recent technical advances in single-cell sequencing and multiplexed spatial imaging have revealed age-related differences in TME composition and function, including key cellular interactions, leading to the development of age-specific prognostic indicators. In addition, advances in our ability to isolate nucleic acids from HRS cells have accelerated our understanding of the molecular alterations in cHL, many of which drive interactions within the TME. Molecular differences in cHL between pediatric/AYA and older adult patients have also emerged. This review summarizes the unique biology of cHL and its TME in children, adolescents, and young adults, highlighting recent breakthroughs in our understanding of cHL biology, differences across the age spectrum, and advances in biomarker development.
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Affiliation(s)
- Tomohiro Aoki
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medicine, University of Toronto, Toronto, ON, United States
| | - Kyle Wierzbicki
- Department of Pediatrics, Weill Cornell Medicine, New York, NY, United States
| | - Suhong Sun
- Department of Pediatrics, Weill Cornell Medicine, New York, NY, United States
| | - Christian Steidl
- Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Lisa Giulino-Roth
- Department of Pediatrics, Weill Cornell Medicine, New York, NY, United States
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14
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Aden D, Zaheer S, Sureka N, Trisal M, Chaurasia JK, Zaheer S. Exploring immune checkpoint inhibitors: Focus on PD-1/PD-L1 axis and beyond. Pathol Res Pract 2025; 269:155864. [PMID: 40068282 DOI: 10.1016/j.prp.2025.155864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 01/20/2025] [Accepted: 02/25/2025] [Indexed: 04/19/2025]
Abstract
Immunotherapy emerges as a promising approach, marked by recent substantial progress in elucidating how the host immune response impacts tumor development and its sensitivity to various treatments. Immune checkpoint inhibitors have revolutionized cancer therapy by unleashing the power of the immune system to recognize and eradicate tumor cells. Among these, inhibitors targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have garnered significant attention due to their remarkable clinical efficacy across various malignancies. This review delves into the mechanisms of action, clinical applications, and emerging therapeutic strategies surrounding PD-1/PD-L1 blockade. We explore the intricate interactions between PD-1/PD-L1 and other immune checkpoints, shedding light on combinatorial approaches to enhance treatment outcomes and overcome resistance mechanisms. Furthermore, we discuss the expanding landscape of immune checkpoint inhibitors beyond PD-1/PD-L1, including novel targets such as CTLA-4, LAG-3, TIM-3, and TIGIT. Through a comprehensive analysis of preclinical and clinical studies, we highlight the promise and challenges of immune checkpoint blockade in cancer immunotherapy, paving the way for future advancements in the field.
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Affiliation(s)
- Durre Aden
- Department of Pathology, Hamdard Institute of Medical science and research, Jamia Hamdard, New Delhi, India.
| | - Samreen Zaheer
- Department of Radiotherapy, Jawaharlal Nehru Medical College, AMU, Aligarh, India.
| | - Niti Sureka
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.
| | - Monal Trisal
- Department of Pathology, Hamdard Institute of Medical science and research, Jamia Hamdard, New Delhi, India.
| | | | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.
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15
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Leivonen S, Karihtala K, Pellinen T, Karjalainen‐Lindsberg M, Aoki T, Steidl C, Leppä S. Characterization of cancer-associated fibroblasts and their spatial architecture reveals heterogeneity and survival associations in classic Hodgkin lymphoma. Hemasphere 2025; 9:e70145. [PMID: 40433553 PMCID: PMC12107116 DOI: 10.1002/hem3.70145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/14/2025] [Accepted: 04/02/2025] [Indexed: 05/29/2025] Open
Abstract
Cancer-associated fibroblasts (CAFs) are a heterogeneous population of stromal cells, which modulate the immune system and can have both pro- and anti-tumorigenic effects. In classic Hodgkin lymphoma (cHL), the role of CAFs has remained largely undefined. We applied multiplexed immunofluorescence imaging and spatial analysis on tumor samples from two independent cHL patient cohorts (n = 131 and n = 148) to study CAFs and their interactions with Hodgkin Reed-Sternberg (HRS) and tumor microenvironment (TME) cells at the single-cell resolution. We show that higher proportions of CAFs are associated with favorable outcomes, independent of the clinical covariables. In contrast, a subset of CD45+ immune cells with strong fibroblast-activation protein positivity, classified as macrophages, was less abundant in nodular sclerosis subtype and associated with worse outcomes. Neighborhood analysis allowed for the identification of colocalization or regional exclusion of phenotypically defined cell types and recurrent cellular neighborhoods. Despite the positive impact of CAF proportions on survival, patients with enrichment of platelet-derived growth factor receptor beta (PDGFRB)-positive CAFs in the vicinity of HRS cells had worse survival in both cohorts, independent of the clinical determinants. Our findings distinguish various subsets of CAFs and macrophages impacting survival in cHL and underscore the importance of the spatial arrangements in the TME.
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Affiliation(s)
- Suvi‐Katri Leivonen
- Research Programs Unit, Applied Tumor Genomics, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- Department of OncologyHelsinki University Hospital Comprehensive Cancer CenterHelsinkiFinland
- iCAN Digital Precision Cancer Medicine FlagshipHelsinkiFinland
| | - Kristiina Karihtala
- Research Programs Unit, Applied Tumor Genomics, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- Department of OncologyHelsinki University Hospital Comprehensive Cancer CenterHelsinkiFinland
- iCAN Digital Precision Cancer Medicine FlagshipHelsinkiFinland
| | - Teijo Pellinen
- Institute for Molecular Medicine Finland (FIMM)HelsinkiFinland
| | | | - Tomohiro Aoki
- Centre for Lymphoid Cancer, BC CancerVancouverBritish ColumbiaCanada
- Princess Margaret Cancer CentreUniversity Health NetworkTorontoOntarioCanada
| | - Christian Steidl
- Centre for Lymphoid Cancer, BC CancerVancouverBritish ColumbiaCanada
| | - Sirpa Leppä
- Research Programs Unit, Applied Tumor Genomics, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- Department of OncologyHelsinki University Hospital Comprehensive Cancer CenterHelsinkiFinland
- iCAN Digital Precision Cancer Medicine FlagshipHelsinkiFinland
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16
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Münz C. Epstein-Barr virus pathogenesis and emerging control strategies. Nat Rev Microbiol 2025:10.1038/s41579-025-01181-y. [PMID: 40281073 DOI: 10.1038/s41579-025-01181-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2025] [Indexed: 04/29/2025]
Abstract
Sixty years after its discovery as the first human tumour virus, Epstein-Barr virus (EBV)-specific therapies and vaccines have entered clinical trials. These might not only be applicable for EBV-associated malignancies, where the virus was originally discovered, but also to immunopathologies, including the autoimmune disease multiple sclerosis, which might be triggered in susceptible individuals by primary EBV infection. This Review discusses the surprisingly large spectrum of diseases that EBV seems to cause, as well as which of these might be treated by the therapeutic approaches that are currently being developed or are already clinically applied. New pharmacological inhibitors, antibody therapies, adoptive T cell therapies and active vaccinations are beginning to offer possibilities to target the various EBV infection programmes that are associated with different diseases. These novel developments might allow us to specifically target EBV rather than its host cells in virus-associated pathologies.
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Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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17
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Huang Y, Sun S, Yin R, Lin Z, Wang D, Wang W, Fu X, Wang J, Lei X, Sun M, Chen S, Wang H. A New Protein-Ligand Trapping System to Rapidly Screen and Discover Small-Molecule Inhibitors of PD-L1 from Natural Products. Molecules 2025; 30:1754. [PMID: 40333811 PMCID: PMC12029895 DOI: 10.3390/molecules30081754] [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: 03/09/2025] [Revised: 04/07/2025] [Accepted: 04/10/2025] [Indexed: 05/09/2025] Open
Abstract
Chinese herbal medicines have played a significant role in the development of new and effective drugs, but how to identify the active ingredients from complex extracts of traditional Chinese herbal medicines was a research difficulty. In recent years, few studies have focused on high-efficiency identification of small-molecule inhibitors of Programmed Death Ligand 1 with lower antigenicity and flexible structure tunability. In order to identify small molecule inhibitors of PD-L1 from complex Chinese herbal extracts, this study established a protein-ligand trapping system based on high-performance liquid chromatography coupled with a photo-diode array detector, ion trap/quadrupole time-of-flight tandem mass spectrometry, and a Programmed Death Ligand 1 affinity chromatography unit (ACPD-L1-HPLC-PDA-IT-TOF (Q-TOF)-MS) to rapidly screen and identify small-molecule inhibitors of Programmed Death Ligand 1 from Toddalia asiatica (L.) Lam. Fourteen components were then identified as PD-L1 binders, and surface plasmon resonance (SPR) validation results showed that six of them-magnoflorine (6), nitidine (22), chelerythrine (24), jatrorrhizine (13), toddaculin (68), and toddanol (45)-displayed PD-L1 binding activity. Laser scanning confocal microscopy results demonstrated that these compounds effectively inhibited the binding of PD-1 to PD-L1 in a dose-dependent manner. Additionally, flow cytometry analysis indicated they could promote human lung cancer cell line (A549) apoptosis when co-cultured with Peripheral Blood Mononuclear Cells (PBMCs). The system's innovation lies in its first integration of dynamic protein-ligand trapping with multi-dimensional validation, coupled with high-throughput screening capacity for structurally diverse natural products. This workflow overcomes traditional phytochemical screening bottlenecks by preserving native protein conformations during affinity capture while maintaining chromatographic resolution, offering a transformative template for accelerating natural product-derived immunotherapeutics through the PD-1/PD-L1 pathway.
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Affiliation(s)
- Yazhuo Huang
- School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; (Y.H.); (J.W.)
| | - Senfeng Sun
- School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; (Y.H.); (J.W.)
| | - Runxin Yin
- School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; (Y.H.); (J.W.)
| | - Zongtao Lin
- Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Daidong Wang
- School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; (Y.H.); (J.W.)
| | - Wanwan Wang
- School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; (Y.H.); (J.W.)
| | - Xiangyu Fu
- School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; (Y.H.); (J.W.)
| | - Jing Wang
- School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; (Y.H.); (J.W.)
| | - Xinyu Lei
- School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; (Y.H.); (J.W.)
| | - Mimi Sun
- School of Pharmacy, Shanxi University of Chinese Medicine, Xianyang 712046, China
| | - Shizhong Chen
- School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; (Y.H.); (J.W.)
| | - Hong Wang
- School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; (Y.H.); (J.W.)
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18
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Zhang C, Wang H, Li X, Jiang Y, Sun G, Yu H. Enhancing antitumor immunity: the role of immune checkpoint inhibitors, anti-angiogenic therapy, and macrophage reprogramming. Front Oncol 2025; 15:1526407. [PMID: 40260303 PMCID: PMC12009726 DOI: 10.3389/fonc.2025.1526407] [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: 11/11/2024] [Accepted: 03/19/2025] [Indexed: 04/23/2025] Open
Abstract
Cancer treatment has long been hindered by the complexity of the tumor microenvironment (TME) and the mechanisms that tumors employ to evade immune detection. Recently, the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic therapies has emerged as a promising approach to improve cancer treatment outcomes. This review delves into the role of immunostimulatory molecules and ICIs in enhancing anti-tumor immunity, while also discussing the therapeutic potential of anti-angiogenic strategies in cancer. In particular, we highlight the critical role of endoplasmic reticulum (ER) stress in angiogenesis. Moreover, we explore the potential of macrophage reprogramming to bolster anti-tumor immunity, with a focus on restoring macrophage phagocytic function, modulating hypoxic tumor environments, and targeting cytokines and chemokines that shape immune responses. By examining the underlying mechanisms of combining ICIs with anti-angiogenic therapies, we also review recent clinical trials and discuss the potential of biomarkers to guide and predict treatment efficacy.
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Affiliation(s)
- Chong Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Xinying Li
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuxin Jiang
- Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guoping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hanqing Yu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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19
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Yi JH, Kim SJ, Kim SA, Jung J, Yoon DH. Nivolumab in Relapsed or Refractory Primary Central Nervous System Lymphoma: Multicenter, Retrospective Study. Cancer Res Treat 2025; 57:590-596. [PMID: 39164085 PMCID: PMC12016817 DOI: 10.4143/crt.2024.531] [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: 06/05/2024] [Accepted: 08/14/2024] [Indexed: 08/22/2024] Open
Abstract
PURPOSE Given that 40%-50% of primary central nervous system lymphoma (PCNSL) tissues exhibit aberrancy on 9p24.1, immune checkpoint inhibitors (ICI) may work for the disease. MATERIALS AND METHODS To define the role of ICIs in PCNSL, we carried out a nationwide retrospect analysis for 22 patients who had been treated with nivolumab monotherapy for relapsed or refractory PCNSL. RESULTS The median age at diagnosis was 66, and male: female ratio was 1:1. Patients received nivolumab after a median of 3 lines (range, 2 to 6) of therapy and at the median age of 67 years (range, 37 to 82 years). Eleven patients (50%) were refractory to the last treatment prior to nivolumab. With a median follow-up duration of 22.3 months (95% confidence interval [CI], 13.1 to 31.5), nine patients (41%) had an objective response (6 complete responses, 3 partial responses), and the median duration of response was 20.9 months (95% CI, 1.7 to 40.0). The median progression-free survival and overall survival were 2.1 months (95% CI, 0.2 to 4.0) and 18.9 months (95% CI, 5.0 to 32.8), respectively. Nivolumab was generally well-tolerated as no patients required dose reduction and only two patients required delay of treatment. CONCLUSION Our study suggests that nivolumab can be a reasonable option with the durable response for RR PCNSL.
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Affiliation(s)
- Jun Ho Yi
- Division of Hematology-Oncology, Department of Medicine, Chung-Ang University, Seoul, Korea
| | - Seok Jin Kim
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang-A Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University, Seongnam, Korea
| | - Jongheon Jung
- Center for Hematologic Malignancies, National Cancer Center, Goyang, Korea
| | - Dok Hyun Yoon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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20
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Kapoor M, Swamy AM, Sundriyal D, Khanna M, Sinha N, J K, Rajaram S, Sehrawat A. Effects of Chemotherapy on Fertility and Fertility Preservation Strategies for the Women of Childbearing Potential Undergoing Chemotherapy: A Comprehensive Review. Indian J Surg Oncol 2025; 16:401-407. [PMID: 40337032 PMCID: PMC12052606 DOI: 10.1007/s13193-024-02103-9] [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: 07/30/2024] [Accepted: 09/19/2024] [Indexed: 01/18/2025] Open
Abstract
Cancer incidence among women of childbearing potential (WCBP) underscores the need for effective fertility preservation strategies. Advances in cancer treatment have significantly improved survival rates, highlighting survivorship issues, particularly fertility concerns in younger patients. Chemotherapy, while a crucial treatment for cancer, often brings with it unintended consequences, particularly regarding fertility. Chemotherapy induces gonadotoxicity through mechanisms such as DNA damage, follicular apoptosis, and hormonal disruption, compromising ovarian function and fertility. The risk of infertility may be low, intermediate, or high depending upon the drug used, the dose, and the duration of use. Quantifying chemotherapy's impact is challenging due to diverse agents and variable effects. Guidelines recommend discussing fertility preservation options with WCBP before treatment, using biomarkers like anti-Mullerian hormone (AMH) to assess ovarian reserve. Strategies include cryopreservation of ovarian tissue, embryos, and oocytes, each with distinct advantages and considerations. Pharmacological interventions like GnRH agonists aim to mitigate gonadotoxic effects, although their efficacy is debated. Surgical approaches like oophoropexy protect ovaries during pelvic radiation but pose logistical challenges. Fertility preservation involves ethical and psychosocial dimensions, including informed consent, financial considerations, and ethical dilemmas, necessitating comprehensive patient counselling. Future research focuses on enhancing techniques such as in vitro maturation, developing artificial ovaries, and refining cryopreservation methods to optimize outcomes.
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Affiliation(s)
- Mayank Kapoor
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Anusha Mruthyunjaya Swamy
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Deepak Sundriyal
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Mridul Khanna
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Nishant Sinha
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Karthik J
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Shalini Rajaram
- Department of Obstretrics and Gynecology, All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Amit Sehrawat
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
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21
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Cosci I, De Toni L, Del Fiore P, Di Nisio A, Carraro S, Radu CM, Bertazza L, Mocellin S, Pigozzo J, Crivellaro G, Coppola M, Ferlin A. Anti-CTLA-and anti-PD-1 immune checkpoint inhibitor antibodies impair human sperm motility in-vitro. Front Pharmacol 2025; 16:1534975. [PMID: 40230698 PMCID: PMC11994717 DOI: 10.3389/fphar.2025.1534975] [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: 11/26/2024] [Accepted: 03/21/2025] [Indexed: 04/16/2025] Open
Abstract
Background Immune checkpoint inhibitors (ICIs), namely, anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody Ipilimumab and anti- and programmed cell death 1 (PD-1) monoclonal antibodies Nivolumab, and Pembrolizumab, have improved the treatment outcomes for many other cancer types. However, their impact on fertility remains under-explored. Methods The possible direct effects of ICIs on human sperm was investigated. Spermatozoa from ten normozoospermic donors were exposed to Ipilimumab, Nivolumab, or Pembrolizumab at concentrations ranging from 1 to 100 ng/mL. Sperm motility was assessed through standard laboratory process. Cell viability and apoptosis markers were evaluated by flow-cytometry using fluorescent Annexin-V probe and Terminal Uridine Nick-End Label (TUNEL) assays. Protein-A-purified therapeutic antibodies (IgG) were also evaluated. Results Spermatozoa had high PD-1 (>99%) and negligible CTLA-4 expression. Exposure to ICIs, was associated with a concentration-dependent impairment of sperm motility, noticeable for Pembrolizumab and Ipilimumab since 10 ng/mL, and for Nivolumab since 100 ng/mL. However, no significant effect on cell apoptosis or viability was shown. Purified IgG from ICIs maintained the adverse effect on cell motility without affecting viability. Conclusion ICIs, specifically Pembrolizumab, Nivolumab, and Ipilimumab, adversely affect human sperm motility in vitro. Further research is required to understand the underlying mechanisms and clinical implications.
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Affiliation(s)
- Ilaria Cosci
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy
| | - Luca De Toni
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy
| | - Paolo Del Fiore
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Andrea Di Nisio
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy
- Department of Health, Nutrition and Sport, Pegaso Telematic University, Naples, Italy
| | - Samuela Carraro
- Department of Medicine, Hematology and Clinical Immunology Branch, University of Padova, Padova, Italy
| | - Claudia Maria Radu
- Department of Medicine, Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, University of Padova, Padova, Italy
| | - Loris Bertazza
- Departiment of Medicine, Unit of Endocrinology, University of Padova, Padova, Italy
| | - Simone Mocellin
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
- Department of Surgical, Oncological and Gastroenterological Sciences (DISCOG), University of Padova, Padova, Italy
| | - Jacopo Pigozzo
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | | | | | - Alberto Ferlin
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy
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22
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Voorhees TJ, McLaughlin EM, Torka P, Florindez J, Kim NH, Moyo TK, Reves H, Sumransub N, Deshpande S, Rose A, Duarte C, Faisal MS, Hamid S, Subbiah S, Ayyappan S, Shea L, Cortese M, Patel K, Major A, Saeed H, Svoboda J, Desai S, Geethakumari PR, Hamadani M, Grover N, Epperla N. Outcomes in patients with classic Hodgkin lymphoma refractory or intolerant to brentuximab vedotin and anti-PD-1 therapy: a real world analysis from 15 U.S. academic centers. Blood Cancer J 2025; 15:45. [PMID: 40140364 PMCID: PMC11947194 DOI: 10.1038/s41408-025-01257-1] [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: 11/25/2024] [Revised: 02/10/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Anti-PD-1 based therapies and brentuximab vedotin (BV) have significantly improved survival in patients with classic Hodgkin lymphoma (cHL) and have been incorporated into earlier lines of therapy. However, there is insufficient data regarding the clinical outcomes in patients who develop refractory disease or who become intolerant of BV and anti-PD-1 therapies (double refractory/intolerant; DR/INT). Here, we evaluated outcomes in patients with DR/INT cHL from 15 US academic medical centers. A total of 173 patients were identified as DR/INT. The median overall survival from the time of cHL diagnosis (OS-1) was 14.8 years (95% CI: 10.9-20.9 years) and the 10-year OS-1 estimate was 62% (95% CI: 52-70%). After accounting for differences in age, patients who underwent autologous stem cell transplant prior to developing DR/INT had significantly longer OS-1 (HR 0.53, 95% CI: 0.29-0.96, p = 0.04). Median OS from time of DR/INT (OS-2) was 7.4 years (95% CI: 4.3-NR) and the 5-year OS-2 estimate was 57% (95% CI: 48-66%). Both anti-PD-1 and BV based therapy rechallenge were effective with median PFS of 237 days (95% CI: 155-357 days) and 183 days (95% CI: 108-273 days), respectively. Finally, advanced therapy options such as CD30 directed chimeric antigen receptor T-cell therapy and allogeneic stem cell transplant after DR/INT were associated with improved OS-2 (p < 0.001). To our knowledge, this represents the largest cohort of patients with DR/INT cHL. OS-2 will serve as a benchmark for future studies aiming to improve survival in DR/INT cHL.
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Affiliation(s)
- Timothy J Voorhees
- Ohio State University, James Comprehensive Cancer Center, Columbus, OH, USA.
| | - Eric M McLaughlin
- Center for Biostatistics, The Ohio State University, Columbus, OH, USA
| | - Pallawi Torka
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jorge Florindez
- University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
| | - Na Hyun Kim
- Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA
| | - Tamara K Moyo
- Atrium Health, Levine Cancer Institute, Charlotte, NC, USA
| | - Heather Reves
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Saarang Deshpande
- University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA
| | | | | | | | - Showkat Hamid
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Suki Subbiah
- Louisiana State University, Stanley S. Scott Cancer Center, New Orleans, LA, USA
| | - Sabarish Ayyappan
- University of Iowa, Holden Comprehensive Cancer Center, Iowa City, IA, USA
| | - Lauren Shea
- University of Alabama at Birmingham, O'Neal Comprehensive Cancer Center, Birmingham, AL, USA
| | - Matt Cortese
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | | | - Ajay Major
- University of Colorado Cancer Center, Aurora, CO, USA
| | | | - Jakub Svoboda
- University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA
| | - Sanjal Desai
- University of Minnesota, Masonic Cancer Center, Minneapolis, MN, USA
| | | | - Mehdi Hamadani
- Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA
| | - Natalie Grover
- University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
| | - Narendranath Epperla
- Ohio State University, James Comprehensive Cancer Center, Columbus, OH, USA
- University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA
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23
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Cristaldi V, Terzi di Bergamo L, Patruno L, Kallikourdis M, Cassanmagnago GA, Corrado F, Calabretta E, Condoluci A, di Trani M, Rahal D, Basso G, Peano C, Graudenzi A, Antoniotti M, Rossi D, Carlo-Stella C. The immune cell dynamics in the peripheral blood of cHL patients receiving anti-PD1 treatment. Front Oncol 2025; 15:1518107. [PMID: 40182035 PMCID: PMC11966435 DOI: 10.3389/fonc.2025.1518107] [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: 10/28/2024] [Accepted: 01/21/2025] [Indexed: 04/05/2025] Open
Abstract
Checkpoint blockade therapy (CBT) involving anti-PD1 antibodies represents the standard approach for cHL patients who do not respond to second-line therapy. Nonetheless, only 20% of relapsed/refractory (R/R) cHL patients treated with CBT achieve complete remission. In this study, we extensively examined the immune dynamics in eight R/R cHL patients treated with CBT, consisting of four complete responders (CR) and four experiencing disease progression (PD), by single cell analysis of peripheral blood mononuclear cells (PBMCs). Our unique approach encompassed longitudinal analysis with three time points, providing a comprehensive understanding of the evolving immune responses during anti-PD1 therapy. Through gene expression profiling, we identified a stable and distinctive KLRG1+/FOS+/JUN+/GZMA+/CD8+ T cell phenotype in patients achieving complete responses. This specific CD8+ T cell subset exhibited sustained activation, underscoring its potential pivotal role in mounting an effective immune response against cHL. Furthermore, T cell receptor (TCR) analysis revealed that in responder patients there is clonal expansion between TCR clonotypes specifically in the KLRG1+/FOS+/JUN+/GZMA+/CD8+ T cell subset. Our longitudinal study offers unique insights into the complex immune dynamics of multiply relapsed/highly pre-treated cHL patients undergoing anti-PD1 therapy.
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Affiliation(s)
- Vanessa Cristaldi
- Department of Biomedical Sciences, Humanitas University, Milano, Italy
| | - Lodovico Terzi di Bergamo
- Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland
- Department of Health Science and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zurich, Switzerland
| | - Lucrezia Patruno
- Department of Informatics, Systems and Communication of the University of Milan-Bicocca, Milan, Italy
| | - Marinos Kallikourdis
- Department of Biomedical Sciences, Humanitas University, Milano, Italy
- Adaptive Immunity Lab, IRCCS Humanitas Research Hospital, Milan, Italy
| | | | - Francesco Corrado
- Department of Oncology and Hematology, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Eleonora Calabretta
- Department of Oncology and Hematology, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Adalgisa Condoluci
- Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland
- Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Martina di Trani
- Department of Biomedical Sciences, Humanitas University, Milano, Italy
| | - Daoud Rahal
- Department of Pathology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Gianluca Basso
- Department of Biomedical Sciences, Humanitas University, Milano, Italy
| | - Clelia Peano
- Institute of Genetics and Biomedical Research, UoS of Milan, National Research Council, Milan, Italy
| | - Alex Graudenzi
- Institute of Molecular Bioimaging and Physiology, Consiglio Nazionale delle Ricerche (IBFM-CNR), Milan, Italy
- Bicocca Bioinformatics, Biostatistic, Bioimaging Centre (B4), Università degli Studi di Milano-Bicocca, Milan, Italy
| | - Marco Antoniotti
- Department of Informatics, Systems and Communication of the University of Milan-Bicocca, Milan, Italy
- Bicocca Bioinformatics, Biostatistic, Bioimaging Centre (B4), Università degli Studi di Milano-Bicocca, Milan, Italy
| | - Davide Rossi
- Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland
- Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Carmelo Carlo-Stella
- Department of Biomedical Sciences, Humanitas University, Milano, Italy
- Department of Oncology and Hematology, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy
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24
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Luo C, Zhang R, Guo R, Wu L, Xue T, He Y, Jin Y, Zhao Y, Zhang Z, Zhang P, Ye S, Li X, Li D, Zhang W, Wang C, Lai L, Pan-Hammarström Q, Wucherpfennig KW, Gao Z, Pan D, Zeng Z. Integrated computational analysis identifies therapeutic targets with dual action in cancer cells and T cells. Immunity 2025; 58:745-765.e9. [PMID: 40023158 DOI: 10.1016/j.immuni.2025.02.007] [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: 10/11/2024] [Accepted: 02/04/2025] [Indexed: 03/04/2025]
Abstract
Many cancer drugs that target cancer cell pathways also impair the immune system. We developed a computational target discovery platform to enable examination of both cancer and immune cells so as to identify pathways that restrain tumor progression and potentiate anti-tumor immunity. Immune-related CRISPR screen analyzer of functional targets (ICRAFT) integrates immune-related CRISPR screen datasets, single-cell RNA sequencing (scRNA-seq) data, and pre-treatment RNA-seq data from clinical trials, enabling a systems-level approach to therapeutic target discovery. Using ICRAFT, we identified numerous targets that enhance both cancer cell susceptibility to immune attack and T cell activation, including tumor necrosis factor (TNF) alpha-induced protein 3 (TNFAIP3), protein tyrosine phosphatase non-receptor type 2 (PTPN2), and suppressor of cytokine signaling 1 (SOCS1). In cancer cells, Tnfaip3 (A20) deletion activated the TNF-nuclear factor kappa-B (NF-κB) pathway, promoting chemokine expression and T cell recruitment to the tumor. T cell-mediated elimination of Tnaifp3-null cancer cells was primarily driven by TNF-induced apoptosis. Inactivation of Tnfaip3 in T cells enhanced anti-tumor efficacy. By integrating diverse functional genomics and clinical datasets, ICRAFT provides an interactive resource toward a deeper understanding of anti-tumor immunity and immuno-oncology drug development.
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Affiliation(s)
- Ce Luo
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China
| | - Rui Zhang
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China
| | - Rui Guo
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China
| | - Lijian Wu
- School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China
| | - Teng Xue
- Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies, Chengdu, Sichuan 610213, China
| | - Yufeng He
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China
| | - Yiteng Jin
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China
| | - Yanping Zhao
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Zongxu Zhang
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China
| | - Peng Zhang
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China
| | - Sitong Ye
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA; Yale School of Medicine, New Haven, CT 06510, USA
| | - Xiaohong Li
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China
| | - Dian Li
- Division of Biology and Biomedical Sciences, Washington University in St. Louis School of Medicine, Saint Louis, MO 63108, USA
| | - Wubing Zhang
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
| | - Chenfei Wang
- Shanghai Putuo District People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Frontier Science Center for Stem Cells, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Luhua Lai
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China; Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies, Chengdu, Sichuan 610213, China
| | - Qiang Pan-Hammarström
- Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17165, Sweden
| | - Kai W Wucherpfennig
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA
| | - Zhidong Gao
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100084, China.
| | - Deng Pan
- School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
| | - Zexian Zeng
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China; Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies, Chengdu, Sichuan 610213, China.
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25
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Gu Y, Fang Y, Guo Y, Yang R, Ma J, Zhang C, Deng M, Wen Q, Gao N, Qiao H. Cytochrome P450 2E1 inhibitor Q11 is effective on hepatocellular carcinoma by promoting peritumor neutrophil chemotaxis. Int J Biol Macromol 2025; 293:139189. [PMID: 39732257 DOI: 10.1016/j.ijbiomac.2024.139189] [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: 10/24/2024] [Revised: 12/04/2024] [Accepted: 12/23/2024] [Indexed: 12/30/2024]
Abstract
Current studies found that the peritumoral tissue of hepatocellular carcinoma (HCC) may be different from normal liver tissue based on proteomics, and related to progression, recurrence and metastasis of HCC. Our previous study proposed "peritumor microenvironment (PME)" to summarize the influence of peritumor tissue on occurrence and progression of HCC. Peritumor CYP2E1 activity was significantly elevated in HCC, and related to occurrence and progression of HCC. However, the effectiveness and mechanism of inhibiting CYP2E1 against HCC remain unclear. In this study, by integrating the advantages of proteomics and transcriptomics, we reanalyzed the various influencing factors in PME. Although there were large differences in the occurrence and progression, the immunity and inflammation still played crucial roles. Peritumor neutrophil were "pro-tumor" phenotype in the stage of progression, while it showed cytotoxicity for tumor cell in the occurrence stage. CYP2E1 activity is associated with peritumor neutrophil infiltration and occurrence of HCC. CYP2E1 inhibitor Q11 showed anti-tumor effects in an orthotopic HCC mouse model by promoting secretion of chemokines and infiltration of neutrophils in peritumor tissue. Overall, these findings provided a reasonable mechanism of anti-tumor effects of CYP2E1 inhibitors, which may be a new strategy for the prevention and treatment of HCC.
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Affiliation(s)
- Yuhan Gu
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; Department of Clinical Pharmacy, Nanyang Central Hospital, Nanyang, China
| | - Yan Fang
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yuanyuan Guo
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Rui Yang
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jun Ma
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Cunzhen Zhang
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Mengyan Deng
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Qiang Wen
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Na Gao
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Hailing Qiao
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
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26
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Gu XY, Gu SL, Chen ZY, Tong JL, Li XY, Dong H, Zhang CY, Qian WX, Ma XC, Yi CH, Yi YX. Uncovering immune cell heterogeneity in hepatocellular carcinoma by combining single-cell RNA sequencing with T-cell receptor sequencing. World J Hepatol 2025; 17:99046. [PMID: 40027555 PMCID: PMC11866147 DOI: 10.4254/wjh.v17.i2.99046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/13/2024] [Accepted: 12/31/2024] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Understanding the status and function of tumor-infiltrating immune cells is essential for improving immunotherapeutic effects and predicting the clinical response in human patients with carcinoma. However, little is known about tumor-infiltrating immune cells, and the corresponding research results in hepatocellular carcinoma (HCC) are limited. AIM To investigate potential biomarker genes that are important for the development of HCC and to understand how immune cell subsets react throughout this process. METHODS Using single-cell RNA sequencing and T-cell receptor sequencing, the heterogeneity and potential functions of immune cell subpopulations from HCC tissue and normal tissue adjacent to carcinoma, as well as their possible interactions, were analyzed. RESULTS Eight T-cell clusters from patients were analyzed and identified using bioinformatics, including six typical major T-cell clusters and two newly identified T-cell clusters, among which Fc epsilon receptor 1G+ T cells were characterized by the upregulation of Fc epsilon receptor 1G, tyrosine kinase binding protein, and T cell receptor delta constant, whereas metallothionein 1E+ T cells proliferated significantly in tumors. Differentially expressed genes, such as regulator of cell cycle, cysteine and serine rich nuclear protein 1, SMAD7 and metallothionein 1E, were identified as significantly upregulated in tumors and have potential as biomarkers. In association with T-cell receptor analysis, we inferred the clonal expansion characteristics of each T-cell cluster in HCC patients. CONCLUSION We identified lymphocyte subpopulations and potential biomarker genes critical for HCC development and revealed the clonal amplification of infiltrating T cells. These data provide valuable resources for understanding the response of immune cell subsets in HCC.
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Affiliation(s)
- Xin-Yu Gu
- Department of Infectious Diseases, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
- Department of General Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Shuang-Lin Gu
- Department of Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Zi-Yi Chen
- Genetic Center, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410078, Hunan Province, China
| | - Jin-Long Tong
- Department of Infectious Diseases, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Xiao-Yue Li
- Department of Infectious Diseases, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Hui Dong
- Department of Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Cai-Yun Zhang
- Department of Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Wen-Xian Qian
- Department of Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Xiu-Chang Ma
- Department of Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Chang-Hua Yi
- Department of Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
- College of Medical Technology, Shaoyang University, Shaoyang 422000, Hunan Province, China
| | - Yong-Xiang Yi
- Department of Infectious Diseases, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China.
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27
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Ge S, Lepic K, Bhindi R, Berg T, Khalaf D, Leber B, Radford M, Walker I, Davies G, Garcia-Horton A. Outcomes of Allogeneic Stem Cell Transplant in Patients with Relapsed/Refractory Hodgkin Lymphoma. Curr Oncol 2025; 32:118. [PMID: 39996918 PMCID: PMC11854641 DOI: 10.3390/curroncol32020118] [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: 01/16/2025] [Revised: 02/05/2025] [Accepted: 02/16/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND The aim of this study was to evaluate real-world clinical outcomes and transplant-related complications of allogeneic stem cell transplantation (alloSCT) for Hodgkin lymphoma (HL). METHODS This was a single-centre, retrospective analysis of relapsed and refractory (R/R) HL patients who received an alloSCT between 1 January 2016 and 29 February 2024 in Hamilton, Ontario. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), non-relapse mortality (NRM), and graft-versus-host disease/relapse-free survival (GRFS). RESULTS Twenty-one patients were identified, with thirteen (62%) pre-treated with programmed death 1 (PD-1) blockade with either nivolumab or pembrolizumab. Seventeen (81%) patients underwent related haploidentical donor transplants, while four (19%) patients received a matched unrelated donor transplant. The 2-year OS and PFS rates were 79% (95% CI: 53-92%) and 63% (95% CI: 37-81%), respectively. Trends towards improved OS, PFS, NRM, and GRFS in PD-1-inhibitor-exposed patients were observed. All PD-1-inhibitor-exposed patients who were in complete remission proceeding to alloSCT remained alive at the last follow-up visit. Among the nine patients in partial remission at the time of alloSCT, three deaths were reported, with a 2-year OS of 61%. CONCLUSIONS Our outcome data of a single-centre, heavily pre-treated cohort of Canadian patients confirm that alloSCT with post-transplant cyclophosphamide-based immunosuppression, which has been associated with improvements in PFS, remains a safe and feasible treatment option for patients with R/R HL in the era of checkpoint inhibitor use.
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Affiliation(s)
- Shiliang Ge
- Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Kylie Lepic
- Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada
| | - Ravi Bhindi
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8P 1H6, Canada
| | - Tobias Berg
- Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada
- Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON L8S 4K1, Canada
- Escarpment Cancer Research Institute, Hamilton Health Sciences, Hamilton, ON L8L 0A4, Canada
| | - Dina Khalaf
- Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada
| | - Brian Leber
- Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Michael Radford
- Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada
| | - Irwin Walker
- Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Gwynivere Davies
- Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada
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Nisar MF, Yan T, Cai Y, Wan C. Immuno-oncological Challenges and Chemoresistance in Veterinary Medicine: Probiotics as a New Strategic Tool. Probiotics Antimicrob Proteins 2025:10.1007/s12602-025-10468-8. [PMID: 39954194 DOI: 10.1007/s12602-025-10468-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2025] [Indexed: 02/17/2025]
Abstract
Cancer has the highest death rates due to increased immuno-oncological (IO) challenges and chemoresistance caused by gut dysbiosis, whereas administration of probiotics may reverse these responses against anticancer therapies. Recently, immunotherapeutics have extensively been focused for significant advancements in pharmacological drug discovery and clinical outcomes. Mammals have intestinal epithelial cells, mucosal immune cells, and indigenous gut microbiota which may reshape immunotherapeutics efficacy. These include use of T-cell immune checkpoint inhibitors (ICPI), genetically engineered T-cells, tumor vaccines, monoclonal antibodies (mAbs), and anti-B- and T-cell antibodies. Immunotherapeutics for cancer treatment became popular in both veterinary and human health care systems due to their strong inhibitory actions against PD-1 and CTLA-4 to check tumorigenesis. IO issues in animals also need special attention, where caninized mAbs targeting CD-20 and CD-52 have been clinically used in treating canine B-cell and T-cell lymphomas, respectively. Probiotics appeared as strong immunotherapeutics that might be shaping the epigenetics of the organisms specifically in animal breeding practices for desired features, but limited literature regarding the immunomodulatory effects in humans and animals is available. In addition, considering the important role of probiotics in humans and veterinary medicine, a new perspective on the probiotic-mediated modulation of ncRNAs (miRNAs, lncRNAs, circRNAs) is also highlighted and would be a new therapeutic tool. This review provides insight into the cellular processes and pharmacological activities for treating veterinary infectious diseases and covers small drug molecules as ncRNA-modulators in veterinary medicine.
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Affiliation(s)
- Muhammad Farrukh Nisar
- Ministry of Education and Jiangxi Key Laboratory of Crop Physiology, Ecology and Genetic Breeding, Jiangxi Agricultural University, Nanchang, 330045, China
- Jiangxi Key Laboratory for Post-harvest Technology and Nondestructive Testing of Fruits & Vegetables, College of Agronomy, Jiangxi Agricultural University, Nanchang, 330045, China
- Department of Physiology and Biochemistry, Cholistan University of Veterinary and Animal Sciences (CUVAS), Bahawalpur, Pakistan
| | - Tingdong Yan
- School of Pharmacy, Nantong University, Nantong, 226001, China.
| | - Yi Cai
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Chunpeng Wan
- Jiangxi Key Laboratory for Post-harvest Technology and Nondestructive Testing of Fruits & Vegetables, College of Agronomy, Jiangxi Agricultural University, Nanchang, 330045, China.
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Sarkozy C, Tessoulin B, Chiron D. Unraveling MCL biology to understand resistance and identify vulnerabilities. Blood 2025; 145:696-707. [PMID: 38551811 DOI: 10.1182/blood.2023022351] [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: 01/29/2024] [Accepted: 03/15/2024] [Indexed: 02/14/2025] Open
Abstract
ABSTRACT Mantle cell lymphoma (MCL) is a rare (5%-7%), aggressive B-cell non-Hodgkin lymphoma with well-defined hallmarks (eg, cyclin D1, SOX11), and its expansion is highly dependent on the tumor microenvironment (TME). Parallel drastic progress in the understanding of lymphomagenesis and improved treatments led to a paradigm shift in this B-cell malignancy with now prolonged disease-free survival after intensive chemotherapy and anti-CD20-based maintenance. However, this toxic strategy is not applicable in frail or older patients, and a small but significant part of the cases present a refractory disease representing unmet medical needs. Importantly, the field has recently seen the rapid emergence of targeted and immune-based strategies with effective combinations relying on biological rationales to overcome malignant plasticity and intratumor heterogeneity. In this review, we expose how unraveling the biology of MCL allows to better understand the therapeutic resistances and to identify neo-vulnerabilities in tumors, which are essential to offer efficient novel strategies for high-risk patients. We first highlight the tumor intrinsic resistance mechanisms and associated Achilles heels within various pathways, such as NF-κB, mitochondrial apoptosis, DNA repair, and epigenetic regulators. We then place the tumor in its complex ecosystem to decipher the dialog with the multiple TME components and show how the resulting protumoral signals could be disrupted with innovative therapeutic strategies. Finally, we discuss how these progresses could be integrated into a personalized approach in MCL.
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Affiliation(s)
- Clémentine Sarkozy
- Service d'Hématologie, Institut Curie, Saint Cloud, France
- Laboratoire d'Imagerie Translationnelle en Oncologie, U1288 Inserm/Institut Curie Centre de Recherche, Paris, France
| | - Benoit Tessoulin
- Service d'Hématologie, Centre Hospitalier Universitaire Nantes, Nantes, France
- reMoVE-B, Nantes Université, INSERM, Centre National de la Recherche Scientifique, Université d'Angers, CRCI2NA, Nantes, France
| | - David Chiron
- reMoVE-B, Nantes Université, INSERM, Centre National de la Recherche Scientifique, Université d'Angers, CRCI2NA, Nantes, France
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30
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Li Y, Yu Y, Lv K, Ge R, Xie X. Prognostic value of body adipose tissue parameters in cancer patients treated with immune checkpoint inhibitors. Front Immunol 2025; 16:1557726. [PMID: 40013137 PMCID: PMC11861556 DOI: 10.3389/fimmu.2025.1557726] [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: 01/09/2025] [Accepted: 01/24/2025] [Indexed: 02/28/2025] Open
Abstract
Objective This study aims to explore the relationship between body adipose tissue characteristics and clinical outcomes in cancer patients receiving immune checkpoint inhibitor (ICI) therapy. Methods We conducted an extensive literature search across three major online databases-Embase, PubMed, and the Cochrane Library-to identify studies examining the link between body adipose tissue and treatment outcomes in cancer patients undergoing ICI therapy, from the inception of each database until February 20, 2024. The quality of the included studies was evaluated using the Newcastle-Ottawa Scale. The primary outcomes analyzed were hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), as well as odds ratios (ORs) for disease control rate (DCR). Pooled estimates and 95% confidence intervals (CIs) were calculated. Results A total of 23 studies were included, encompassing 2741 cancer patients. The analysis revealed that patients with higher levels of visceral adipose tissue (VAT) exhibited significantly improved OS (HR: 0.72, 95% CI: 0.59-0.89, p < 0.001) and PFS (HR: 0.80, 95% CI: 0.67-0.96, p = 0.015), along with a higher DCR (OR: 1.81, 95% CI: 1.26-2.60, p = 0.001), compared to those with lower VAT levels. Additionally, increased subcutaneous adipose tissue (SAT) levels were associated with significantly better OS (HR: 0.69, 95% CI: 0.58-0.82, p < 0.001) and PFS (HR: 0.82, 95% CI: 0.68-1.00, p = 0.049), and a higher DCR (OR: 1.99, 95% CI: 1.15-3.44, p = 0.014). Elevated total adipose tissue (TAT) levels were also linked to longer OS (HR: 0.73, 95% CI: 0.55-0.97, p = 0.028). However, a higher visceral-to-subcutaneous adipose tissue ratio (VSR) was associated with a shorter OS (HR: 1.43, 95% CI: 1.09-1.87, p = 0.010). No significant relationship was found between TAT (HR: 0.81, 95% CI: 0.54-1.23, p = 0.332) and VSR (HR: 1.20, 95% CI: 0.95-1.51, p = 0.131) with PFS in ICI-treated patients. Conclusion This study highlights the prognostic relevance of VAT and SAT in predicting treatment response and survival outcomes in cancer patients receiving ICIs. These findings suggest that assessments of VAT and SAT should be incorporated into prognostic evaluations for this patient population.
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Affiliation(s)
- Yan Li
- Department of Traditional Chinese Medicine, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan, China
| | - Yean Yu
- Department of Nephrology, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan, China
| | - Kun Lv
- Department of Traditional Chinese Medicine, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan, China
| | - Rongjuan Ge
- Department of Traditional Chinese Medicine, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan, China
| | - Xie Xie
- Department of Traditional Chinese Medicine, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan, China
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Guo X, Nie H, Zhang W, Li J, Ge J, Xie B, Hu W, Zhu Y, Zhong N, Zhang X, Zhao X, Wang X, Sun Q, Wei K, Chen X, Ni L, Zhang T, Lu S, Zhang L, Dong C. Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer. Cancer Cell 2025; 43:248-268.e9. [PMID: 39889705 DOI: 10.1016/j.ccell.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 09/04/2024] [Accepted: 01/06/2025] [Indexed: 02/03/2025]
Abstract
Combination of anti-PD-1 with lenvatinib showed clinical efficacy in multiple cancers, yet the underlying immunological mechanisms are unclear. Here, we compared T cells in hepatocellular carcinoma (HCC) patients before and after combination treatment using single-cell transcriptomics and T cell receptor (scTCR) clonotype analyses. We found that tumor-infiltrating GZMK+ CD8+ effector/effector memory T (Teff/Tem) cells, showing a favorable response to combination therapy, comprise progenitor exhausted T (Tpex) cells and also unappreciated circulating Tem (cTem) cells enriched with hepatitis B virus (HBV) specificity. Further integrated analyses revealed that cTem cells are specifically associated with responsiveness to the combination therapy, whereas Tpex cells contribute to responses in both combination therapy and anti-PD-1 monotherapy. Notably, an underexplored KIR+ CD8+ T cell subset in the tumor and FOXP3+ CD4+ regulatory T cells are specifically enriched in non-responders after the combination therapy. Our study thus elucidated T cell subsets associated with clinical benefits and resistance in cancer immunotherapy.
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Affiliation(s)
- Xinyi Guo
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Hu Nie
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518132, China; State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
| | - Wenwen Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital / Key Laboratory of Digital Hepatobiliary Surgery, PLA / Institute of Hepatobiliary Surgery of Chinese PLA, Beijing 100953, China
| | - Jiesheng Li
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518132, China; State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
| | - Jing Ge
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China
| | - Bowen Xie
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Wenbo Hu
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yicheng Zhu
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China
| | - Na Zhong
- Shenzhen Peacock Biotechnology Co., Ltd, Shenzhen, Guangdong 518112, China
| | - Xinmei Zhang
- Shenzhen Peacock Biotechnology Co., Ltd, Shenzhen, Guangdong 518112, China
| | - Xiaohong Zhao
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xiaoshuang Wang
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Qinli Sun
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Kun Wei
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xiaoyuan Chen
- Tsinghua Clinical Research Institute, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Ling Ni
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ting Zhang
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China
| | - Shichun Lu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital / Key Laboratory of Digital Hepatobiliary Surgery, PLA / Institute of Hepatobiliary Surgery of Chinese PLA, Beijing 100953, China.
| | - Lei Zhang
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518132, China; State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China; Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, Guangdong 518107, China.
| | - Chen Dong
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Research Unit of Immune Regulation and Immune Diseases (2022RU001), Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Westlake University School of Medicine, Hangzhou, Zhejiang 310030, China.
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Kan S, Bai H, Liu H, Cui J, Ke X, Zhang H, Liu L, Yan D, Jiang Y, Zang A, Qi J, Wang L, Liu Z, Xu B, Zhang Y, Zhang Z, Zhao X, Hu C, Yang S, Zhou H, Shi J, Shao Z, Xiang Y, Lin N, Zhang M. Long-term follow-up of zimberelimab in relapsed or refractory classic Hodgkin lymphoma: Insights from the phase Ⅱ YH-S001-04 clinical trial. Leuk Res 2025; 149:107633. [PMID: 39799811 DOI: 10.1016/j.leukres.2024.107633] [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: 08/14/2024] [Revised: 11/16/2024] [Accepted: 11/25/2024] [Indexed: 01/15/2025]
Abstract
BACKGROUND Treating relapsed or refractory classical Hodgkin lymphoma (R/R cHL) remains challenging. This report extends the three-year follow-up period for the phase Ⅱ YH-S001-04 trial, expanding upon the initial 15.8-month analysis. METHODS Zimberelimab 240 mg was administered every two weeks for two years or until disease progression or death. The endpoint was the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS The median follow-up was 38.0 months (3.5-42.8 months). The ORR was 91.6 % (95 % CI, 83.8-95.9). Median PFS was 23.6 months, with a longer PFS in responders (28.5 months) compared to non-responders (9.2 months) (P=0.0098). Complete responders had longer mPFS than partial responders (Not reached vs. 28.5 months, P=0.3469). Relapsed patients had improved mPFS compared to refractory cHL (23.6 vs. 10.6 months, P=0.0061). Patients with <3 lines of therapy showed longer mPFS compared to ≥3 lines (not reached vs. 23.6 months, P=0.0095). The 3-year OS rate was 94.0 % (95 % CI, 85.9-97.4). No serious adverse events with incidence >5 %. CONCLUSIONS With encouraging data on both PFS and OS, zimberelimab demonstrates ongoing efficacy and safety in treating R/R cHL, supporting zimberelimab as an effective treatment alternative for R/R cHL (NCT03655483).
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MESH Headings
- Humans
- Hodgkin Disease/drug therapy
- Hodgkin Disease/pathology
- Hodgkin Disease/mortality
- Adult
- Male
- Female
- Middle Aged
- Follow-Up Studies
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Young Adult
- Aged
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/mortality
- Adolescent
- Drug Resistance, Neoplasm/drug effects
- Survival Rate
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Affiliation(s)
- Suisui Kan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hai Bai
- Department of Hematology, 940 Hospital of the Joint Logistic Support Force of the PLA, Lanzhou, China
| | - Hui Liu
- Department of Hematology, Beijing Hospital, Beijing, China
| | - Jie Cui
- Department of Hematology, Gansu Province Cancer Hospital, Lanzhou, China
| | - Xiaoyan Ke
- Department of Hematology, Peking University Third Hospital, Beijing, China
| | - Huilai Zhang
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Lihong Liu
- Department of Hematology, Fourth Hospital of Hebei Medical University, Tumor Hospital of Hebei Province, Shijiazhuang, China
| | - Dongmei Yan
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yongsheng Jiang
- Department of Oncology, Tongji Hospital, Tongji Medical College Huazhong University of Science & Technology, Wuhan, China
| | - Aimin Zang
- Department of Medical Oncology, The Affiliate Hospital of Hebei Medical University, Baoding, China
| | - Junyuan Qi
- Department of Lymphoma, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China
| | - Li Wang
- Department of Hematology, Jiangsu Province Hospital, Nanjing, China
| | - Zhuogang Liu
- Department of Hematology, Sheng Jing Hospital of China Medical University, Shenyang, China
| | - Bing Xu
- Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Ying Zhang
- Department of Oncology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, China
| | - Zhihui Zhang
- Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Chengdu, China
| | - Xielan Zhao
- Department of Hematology, Xiangya Hospital Central South University, Changsha, China
| | - Chunhong Hu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shenmiao Yang
- Department of Hematology, Peking University People's Hospital, Beijing, China
| | - Hui Zhou
- Department of Lymphoma and Hematology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangyi School of Medicine, Central South University, Changsha, China
| | - Jinsheng Shi
- Department of Oncology, Cangzhou People's Hospital, Cangzhou, China
| | - Zonghong Shao
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Ying Xiang
- Department of Hematology and Oncology, Chongqing Cancer Hospital, Chongqing, China
| | - Ningjing Lin
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), The Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Takahashi H, Ito S, Nakanishi Y, Miura K, Nishimaki H, Nakagawa M, Otake S, Hamada T, Koike T, Iizuka K, Masuda S, Nakayama T, Shimizu T, Ishibashi N, Kogure H, Nakamura H. Topological importance of CD8 + T-cell enrichment in the tumor microenvironment of classic Hodgkin lymphoma. Ann Hematol 2025; 104:1047-1057. [PMID: 39820429 PMCID: PMC11971151 DOI: 10.1007/s00277-025-06189-1] [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: 05/22/2024] [Accepted: 01/03/2025] [Indexed: 01/19/2025]
Abstract
Classic Hodgkin lymphoma (CHL) histologically consists of Hodgkin Reed-Sternberg (HRS) cells and the tumor microenvironment (TME), but the relationship between TME characteristics and clinical features of CHL remains unclear. We aimed to investigate the effects of the TME structure on the outcomes of patients with CHL. We performed a high-throughput analysis of HRS cells and their topological relationship with the reactive immune cells in the TME. After multiplexed immunofluorescence labeling against CD4, CD8, CD30, CD68, CD163, PD-1, and PD-L1, visual images were analyzed. Phenotypes were assigned to all reactive cells, such as CD4+ and CD8+ T-cells and macrophages. Since the densities of PD1+/CD4+ T-cells, CD8+ T-cells, and PD-L1+ macrophages were significantly higher in the area < 60 μm than in the area < 120 μm from each HRS cell in 45 tissue samples from 34 patients with CHL, we further analyzed the TME-component cells by focusing on the 60 μm radius in the initial samples. TMEs containing > 15 CD8+ T-cells were associated with a significantly better 3-year progression-free survival than those with ≤ 15 CD8+ T-cells (100% vs. 53%, p = 0.006). In comparison with TMEs containing ≤ 15 CD8+ T-cells, TMEs containing > 15 CD8+ T-cells had significantly more PD-L1- macrophages (mean 3 vs. 1 cell, p = 0.015) and fewer PD-1+/CD4+ T-cells (mean 16 vs. 28 cells, p = 0.036). Epstein-Barr virus positivity in HRS cells was significantly associated with a higher number of macrophages in the 60 μm radius area. In conclusion, the TME structure in patients with CHL can differ, enabling precision therapies.
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Affiliation(s)
- Hiromichi Takahashi
- Department of Medicine Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
| | - Shun Ito
- Department of Medicine Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
| | - Yoko Nakanishi
- Department of Pathology and Microbiology Division of Oncologic Pathology, Nihon University School of Medicine, Tokyo, Japan
| | - Katsuhiro Miura
- Department of Medicine Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan.
- Department of Medicine, Division of Hematology and Rheumatology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi City, Tokyo, 173-8610, Japan.
| | - Haruna Nishimaki
- Department of Pathology and Microbiology Division of Oncologic Pathology, Nihon University School of Medicine, Tokyo, Japan
| | - Masaru Nakagawa
- Department of Medicine Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
- Present Address: Department of Hematology, Kasukabe Medical Center, Saitama, Japan
| | - Shimon Otake
- Department of Medicine Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
| | - Takashi Hamada
- Department of Medicine Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
| | - Takashi Koike
- Department of Medicine Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
| | - Kazuhide Iizuka
- Department of Medicine Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
- Department of Pathology and Microbiology Division of Laboratory Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Shinobu Masuda
- Department of Pathology and Microbiology Division of Oncologic Pathology, Nihon University School of Medicine, Tokyo, Japan
| | - Tomohiro Nakayama
- Department of Pathology and Microbiology Division of Laboratory Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Tetsuo Shimizu
- Department of Medicine, Division of Respiratory Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Naoya Ishibashi
- Department of Radiology, Nihon University School of Medicine, Tokyo, Japan
| | - Hirofumi Kogure
- Department of Medicine Division of Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan
| | - Hideki Nakamura
- Department of Medicine Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
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Lurain K, Ramaswami R, Ekwede I, Eulo V, Goyal G, Menon M, Odeny TA, Sharon E, Wagner MJ, Wang CC(J, Bhardwaj N, Friedlander PA, Abdul-Hay M, Castro EMC, Labo N, Marshall VA, Miley W, Moore K, Roshan R, Whitby D, Kask AS, Kaiser J, Han E, Wright A, Yarchoan R, Fling SP, Uldrick TS. Cancer Immunotherapy Trials Network 12: Pembrolizumab in HIV-Associated Kaposi Sarcoma. J Clin Oncol 2025; 43:432-442. [PMID: 39356983 PMCID: PMC11779594 DOI: 10.1200/jco.24.00640] [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: 03/26/2024] [Revised: 06/21/2024] [Accepted: 08/12/2024] [Indexed: 10/04/2024] Open
Abstract
PURPOSE Cancer Immunotherapy Trials Network 12 demonstrated safety of pembrolizumab in treating advanced cancer in people with HIV. Here, we report results of the Kaposi sarcoma (KS) cohort. METHODS In this multicenter phase I trial, we enrolled participants with HIV-associated KS on antiretroviral therapy with CD4+ ≥50 cells/μL and HIV plasma RNA <200 copies/mL. Pembrolizumab 200 mg intravenously was administered once every 3 weeks for up to 35 cycles. The primary end point was safety, and the secondary end point was KS response by modified AIDS Clinical Trials Group Criteria. RESULTS Thirty-two cisgender men enrolled with baseline median CD4+ T-cell count of 274 cells/µL. All but nine participants had received previous systemic KS therapy. Participants received a median of 11 cycles of pembrolizumab (range, 1-35). Sixty-six percent had grade ≥1 treatment-emergent adverse events, including one death from polyclonal KS herpesvirus-related B-cell lymphoproliferation. Thirty-one percent had ≥one immune-mediated AEs (imAEs) with 25% requiring systemic steroids. In 29 participants with evaluable KS, the overall response rate (ORR) was 62.1% (95% CI, 42.3 to 79.3) and did not differ by CD4+ T-cell count. ORR in the eight participants with evaluable disease without previous KS therapy was 87.5% (95% CI, 47.3 to 99.7). Median duration of response (DOR) was not reached, and the Kaplan-Meier estimate of DOR of ≥12 months was 92.3% (95% CI, 56.6 to 98.8). Median progression-free survival was 28.2 months (95% CI, 4.2 to noncalculable). CONCLUSION Pembrolizumab yielded a high rate of durable responses in HIV-associated KS. imAEs were successfully managed with standard guidelines.
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MESH Headings
- Humans
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Male
- Middle Aged
- Sarcoma, Kaposi/drug therapy
- Sarcoma, Kaposi/immunology
- Sarcoma, Kaposi/virology
- Sarcoma, Kaposi/mortality
- Adult
- HIV Infections/drug therapy
- HIV Infections/complications
- HIV Infections/immunology
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/adverse effects
- AIDS-Related Opportunistic Infections/drug therapy
- AIDS-Related Opportunistic Infections/immunology
- Immune Checkpoint Inhibitors/adverse effects
- Immune Checkpoint Inhibitors/therapeutic use
- Aged
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Affiliation(s)
- Kathryn Lurain
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ramya Ramaswami
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Irene Ekwede
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Vanessa Eulo
- University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gaurav Goyal
- University of Alabama at Birmingham, Birmingham, AL, USA
| | - Manoj Menon
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
| | - Thomas A. Odeny
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Elad Sharon
- Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | - Michael J. Wagner
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Nina Bhardwaj
- Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA
| | | | - Maher Abdul-Hay
- Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, New York, NY, USA
| | - Elena M. Cornejo Castro
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Nazzarena Labo
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Vickie Ann Marshall
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Wendell Miley
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Kyle Moore
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Romin Roshan
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Denise Whitby
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Angela Shaulov Kask
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
| | - Judith Kaiser
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
| | - Emma Han
- Cytel (Shanghai) Co. Ltd, Shanghai, China
| | - Anna Wright
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Steven P. Fling
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
| | - Thomas S. Uldrick
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
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Amouin S, Brureau L, Parnot C, Picchi H, Le Roy A, Barhli A, Audisio MA, Pautas M, Brezun J, Schernberg A, Vanquaethem H, Helissey C. Optimizing the management of immune-related adverse events and survival in patients with thoracic cancer receiving immunotherapy through artificial intelligence (electronic patient-reported outcomes): The IMPATHI study. Bull Cancer 2025; 112:149-156. [PMID: 39701887 DOI: 10.1016/j.bulcan.2024.11.004] [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: 07/20/2024] [Revised: 11/04/2024] [Accepted: 11/05/2024] [Indexed: 12/21/2024]
Abstract
INTRODUCTION The lung cancer continues to be the primary cause of cancer-related deaths, despite significant advancements in treatment through the introduction of immunological checkpoint inhibitors (ICI). These inhibitors, initially used as monotherapy, are now employed in combined therapies, resulting in improved survival rates. The ICI function by restoring T-cell activity to target tumor cells, but may lead to undesirable immune-related adverse events (irAE), necessitating careful management. METHODS The IMPATHI study, a prospective observational study conducted at the Begin Military Hospital, evaluated patient adherence to ePRO-based telemonitoring using the Cureety platform. The study included patients with advanced thoracic cancer receiving immunotherapy. Minors and those who did not consent to digital surveillance were excluded. Patients filled out ePRO questionnaires, and their health status was classified into four levels. The primary objective was compliance evaluation, with secondary objectives including tolerance profile and impact on survival. RESULTS The study recruited 22 patients, with a median age of 66years. Adenocarcinoma was the most common diagnosis, and 91% of patients had metastatic disease. Patient adherence to the telemonitoring platform was 83.3%, with 64% of responses indicating stable conditions. Common adverse events included asthenia, dyspnea, and joint/muscle pain. The 24-month progression-free survival rate was 79%, and the overall survival rate was 71.1%. CONCLUSION The IMPATHI study demonstrates the potential of telemonitoring in the management of lung cancer patients receiving ICI therapy, with high compliance and promising survival outcomes. Telemonitoring offers significant benefits in early detection of adverse events and personalized care to patients. Future efforts should focus on expanding access to telemonitoring for all patients.
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Affiliation(s)
- Serge Amouin
- Department of Medical Oncology and Clinical Research Unit, Military Hospital Bégin, Saint-Mandé, France
| | - Laurent Brureau
- Department of Urology, CHU de Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe
| | | | - Hugo Picchi
- Department of Medical Oncology and Clinical Research Unit, Military Hospital Bégin, Saint-Mandé, France
| | - Audrey Le Roy
- Department of Medical Oncology and Clinical Research Unit, Military Hospital Bégin, Saint-Mandé, France
| | - Aline Barhli
- Department of Medical Oncology and Clinical Research Unit, Military Hospital Bégin, Saint-Mandé, France
| | - Marie-Anne Audisio
- Department of Medical Oncology and Clinical Research Unit, Military Hospital Bégin, Saint-Mandé, France
| | - Marie Pautas
- Department of Medical Oncology and Clinical Research Unit, Military Hospital Bégin, Saint-Mandé, France
| | - Juliette Brezun
- Department of Medical Oncology and Clinical Research Unit, Military Hospital Bégin, Saint-Mandé, France
| | - Antoine Schernberg
- Department of Medical Oncology and Clinical Research Unit, Military Hospital Bégin, Saint-Mandé, France
| | - Hélène Vanquaethem
- Department of Internal Medicine, Military Hospital Bégin, Saint-Mandé, France
| | - Carole Helissey
- Department of Medical Oncology and Clinical Research Unit, Military Hospital Bégin, Saint-Mandé, France.
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Khilar S, Dembinska-Kenner A, Hall H, Syrmos N, Ligarotti GKI, Plaha P, Apostolopoulos V, Chibbaro S, Barbagallo GMV, Ganau M. Towards a New Dawn for Neuro-Oncology: Nanomedicine at the Service of Drug Delivery for Primary and Secondary Brain Tumours. Brain Sci 2025; 15:136. [PMID: 40002469 PMCID: PMC11852924 DOI: 10.3390/brainsci15020136] [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: 12/12/2024] [Revised: 01/21/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
(1) Background/Objectives: Primary and secondary brain tumours often hold devastating prognoses and low survival rates despite the application of maximal neurosurgical resection, and state-of-the-art radiotherapy and chemotherapy. One limiting factor in their management is that several antineoplastic agents are unable to cross the blood-brain barrier (BBB) to reach the tumour microenvironment. Nanomedicine could hold the potential to become an effective means of drug delivery to overcome previous hurdles towards effective neuro-oncological treatments. (2) Methods: A scoping review following the PRISMA-ScR guidelines and checklist was conducted using key terms input into PubMed to find articles that reflect emerging trends in the utilisation of nanomedicine in drug delivery for primary and secondary brain tumours. (3) Results: The review highlights various strategies by which different nanoparticles can be exploited to bypass the BBB; we provide a synthesis of the literature on the ongoing contributions to therapeutic protocols based on chemotherapy, immunotherapy, focused ultrasound, radiotherapy/radiosurgery, and radio-immunotherapy. (4) Conclusions: The emerging trends summarised in this scoping review indicate encouraging advantageous properties of nanoparticles as potential effective drug delivery mechanisms; however, there are still nanotoxicity issues that largely remain to be addressed before the translation of these innovations from laboratory to clinical practice.
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Affiliation(s)
- Smita Khilar
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
| | - Antonina Dembinska-Kenner
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
| | - Helen Hall
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
| | - Nikolaos Syrmos
- School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | | | - Puneet Plaha
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
| | - Vasileios Apostolopoulos
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
| | - Salvatore Chibbaro
- Neurosurgery Unit, Department of Medical and Surgical Sciences and Neurosciences, Siena University, 53100 Siena, Italy
| | | | - Mario Ganau
- Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 0AG, UK; (S.K.); (H.H.)
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
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37
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Li S, Pan Y, Ye R, Wang Y, Li L. Immune checkpoints in B-cell Lymphoma: Still an Unmet challenge from Basic research to clinical practice. Int Immunopharmacol 2025; 146:113717. [PMID: 39673995 DOI: 10.1016/j.intimp.2024.113717] [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: 08/11/2024] [Revised: 11/24/2024] [Accepted: 11/24/2024] [Indexed: 12/16/2024]
Abstract
In the last decade, advancements in immunotherapy knowledge have highlighted CTLA-4, PD-1, LAG-3, TIM-3, and TIGIT, decisive immune checkpoints exhibiting within the tumor microenvironment (TME), as fundamental objects for cancer immunotherapy. The widespread clinical use of immune checkpoint inhibitors (ICls), employing PD-1/PD-L1 or CTLA-4 antibodies to obstruct crucial checkpoint regulators, is noted in treating B-cell lymphoma patients. Nevertheless, the prolonged advantages of the currently employed treatments against CTLA-4, PD-1, and PD-L1 are uncommon among patients. Thus, recent focus has been progressively moved to additional immune checkpoints on T cells, like LAG-3, TIM-3, and TIGIT, which are now seen as reassuring targets for treatment and broadly acknowledged. There are several types of immunecheckpoint molecules expressed by T cells, and inhibitors targeting immune checkpoints can revive and amplify the immune response of T lymphocytes against tumors, a crucial aspect in lymphoma therapy. However, there is little knowledge about their regulation. Herein, we discuss the anti-tumor effects and functions of ICIs in controlling T-cell activity, as well as the progress in combined application with other immunotherapies.
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Affiliation(s)
- Sijia Li
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, PR China
| | - Yuanyuan Pan
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, PR China
| | - Ruyu Ye
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, PR China
| | - Yu Wang
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, PR China
| | - Li Li
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, PR China.
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38
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Tian Y, Peng X, Yang X. Decreased PD-L1 contributes to preeclampsia by suppressing GM-CSF via the JAK2/STAT5 signal pathway. Sci Rep 2025; 15:3124. [PMID: 39856320 PMCID: PMC11759946 DOI: 10.1038/s41598-025-87349-1] [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: 04/11/2024] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
Programmed cell death protein 1 (PD-1) and its ligand PD-L1 have been detected at the materno-embryonic interface in both human and murine pregnancy models. However, research regarding the PD-1/PD-L1 signal in preeclampsia (PE) is limited. In the present investigation, 30 normal pregnant females and 30 PE patients were enrolled. Cellular functional experiments were performed in two trophoblast cell lines by transfection with lentiviral vectors for overexpression and down-regulation of PD-L1. The placental expressions of PD-1, PD-L1, and granulocyte macrophage colony-stimulating factor (GM-CSF) exhibited a notable reduction in PE cases compared with healthy pregnancies. Cellular functional experiments indicated that excessive PD-L1 expression significantly enhanced trophoblast migratory, invasive, and proliferative capabilities while inhibiting cell apoptosis. Additionally, the administration of lentivirus-mediated PD-L1 overexpression could alleviate clinical symptoms (hypertension, proteinuria) of PE-like rats. Therefore, decreased PD-L1 may contribute to PE by inhibiting GM-CSF via activating the JAK2/STAT5 pathway. Our study provides a novel pathway that can be targeted for the therapy of this disease.
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Affiliation(s)
- Yingying Tian
- Department of Obstetrics, The First Hospital of China Medical University, Shenyang, 110000, Liaoning, China
| | - Xu Peng
- Department of Obstetrics, The First Hospital of China Medical University, Shenyang, 110000, Liaoning, China
| | - Xiuhua Yang
- Department of Obstetrics, The First Hospital of China Medical University, Shenyang, 110000, Liaoning, China.
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39
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Dong Y, Cheng A, Zhou J, Guo J, Liu Y, Li X, Chen M, Hu D, Wu J. PRDX2 induces tumor immune evasion by modulating the HDAC3-Galectin-9 axis in lung adenocarcinoma cells. J Transl Med 2025; 23:81. [PMID: 39825365 PMCID: PMC11740609 DOI: 10.1186/s12967-024-05888-z] [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: 05/09/2024] [Accepted: 11/14/2024] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND PRDX2 is significantly expressed in various cancers and is associated with the proliferation of tumor cells. Nonetheless, the precise mechanism of PRDX2 in tumor immunity remains incompletely understood. This study aims to investigate the impact of PRDX2, which is highly expressed in lung adenocarcinoma, on T cells in the tumor immune microenvironment, and its immune action target to promote the immune escape of lung cancer cells, to provide a theoretical basis for lung adenocarcinoma treatment with PRDX2 as the target. METHODS Mouse animal models to verify the effect of Conoidin A treatment on tumor growth and T cell infiltration. Flow cytometry and Western blot verified tumor cell apoptosis in the in vitro co-culture system as well as granzyme B and perforin expression in T cells. RNA-Seq was used to obtain the downstream immune molecule. si-RNA knockdown of Galectin-9 was co-cultured with T cells in vitro. Immunofluorescence and Western blot verified that PRDX2 regulates Galectin-9 expression through HDAC3. RESULTS PRDX2 expression was negatively correlated with CD8+ T cell expression in LUAD patients. Inhibition of PRDX2 significantly enhanced T-cell killing of LUAD cells and reduced tumor load in both in vitro and in vivo models. Mechanistically, Conoidin A or shRNA_PRDX2 decreased Galectin-9 expression by down-regulating the phosphorylation of HDAC3, consequently enhancing the infiltration and function of CD8+ T cells. CONCLUSIONS This study reveals the role of the PRDX2/HDAC3/Galectin-9 axis in LUAD immune escape and indicates Galectin-9 as a promising target for immunotherapy.
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Affiliation(s)
- Yunjia Dong
- School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, 232000, China
- Anhui Occupational Health and Safety Engineering Laboratory, Huainan, Anhui, 232000, China
| | - Anqi Cheng
- School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, 232000, China
- Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, Anhui, 232000, China
| | - Jiawei Zhou
- School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, 232000, China
- Anhui Occupational Health and Safety Engineering Laboratory, Huainan, Anhui, 232000, China
| | - Jianqiang Guo
- School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, 232000, China
- Anhui Occupational Health and Safety Engineering Laboratory, Huainan, Anhui, 232000, China
| | - Yafeng Liu
- School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, 232000, China
- Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, Anhui, 232000, China
| | - Xuan Li
- School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, 232000, China
- Anhui Occupational Health and Safety Engineering Laboratory, Huainan, Anhui, 232000, China
| | - Maoqian Chen
- School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, 232000, China
- Anhui Occupational Health and Safety Engineering Laboratory, Huainan, Anhui, 232000, China
| | - Dong Hu
- The First Affiliated Hospital of Anhui University of Science and Technology (Huainan First People's Hospital, School of Medicine), Huainan, Anhui, 232000, China.
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 232001, China.
| | - Jing Wu
- Joint Research Center for Occupational Medicine and Health of IHM, School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, 232000, China.
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40
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Kwang AC, Duran GE, Fernandez-Pol S, Najidh S, Li S, Bastidas Torres AN, Wang EB, Herrera M, Bandali TI, Kurtz DM, Kim YH, Khodadoust MS. Genetic alteration of class I HLA in cutaneous T-cell lymphoma. Blood 2025; 145:311-324. [PMID: 39388712 PMCID: PMC11775508 DOI: 10.1182/blood.2024024817] [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: 04/15/2024] [Revised: 09/18/2024] [Accepted: 09/30/2024] [Indexed: 10/12/2024] Open
Abstract
ABSTRACT Abnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCLs). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides or Sézary syndrome. Targeted DNA sequencing, including coverage of HLA loci, revealed at least 1 HLA abnormality in 26 of 65 patients (40%). Twelve unique somatic HLA mutations were identified across 9 patients, and loss of heterozygosity or biallelic loss of HLA was found to affect 24 patients. Although specific HLA alleles were commonly disrupted, these events did not associate with a decrease in the total class I HLA expression. Genetic events preferentially disrupted HLA alleles capable of presenting greater numbers of putative neoantigens. HLA abnormalities co-occurred with other genetic immune evasion events and were associated with worse progression-free survival. Single-cell analyses demonstrated that HLA abnormalities were frequently subclonal. Through analysis of serial samples, we observed that disrupting class I HLA events change dynamically over the disease course. The dynamics of HLA disruption are highlighted in a patient who received pembrolizumab and in whom resistance to pembrolizumab was associated with the elimination of an HLA mutation. Overall, our findings show that genomic class I HLA abnormalities are common in advanced CTCL and may be an important consideration in understanding the effects of immunotherapy in CTCL.
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Affiliation(s)
- Alexa C. Kwang
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - George E. Duran
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA
| | | | - Safa Najidh
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Shufeng Li
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA
| | | | - Erica B. Wang
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA
| | - Melba Herrera
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA
| | - Tarek I. Bandali
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA
| | - David M. Kurtz
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Youn H. Kim
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA
| | - Michael S. Khodadoust
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA
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Adashek JJ, Munoz JL, Kurzrock R. If it is a solid tumor target, then it may be a hematologic cancer target: Bridging the great divide. MED 2025; 6:100550. [PMID: 39689708 PMCID: PMC11725447 DOI: 10.1016/j.medj.2024.11.003] [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: 04/26/2024] [Revised: 10/01/2024] [Accepted: 11/01/2024] [Indexed: 12/19/2024]
Abstract
Tumor-agnostic US Food and Drug Administration approvals are transforming oncology. They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAFV600E mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers). Pemigatinib is approved for FGFR1-rearranged myeloid/lymphoid neoplasms. The genomically driven tissue-agnostic approach has a strong biological rationale (cancer is a disease of the genome), yields remarkably high response rates, and provides drug access to patients with an unmet need (rare/ultra-rare malignancies). Despite the solid tumor focus, both solid and hematologic cancers can harbor identical driver molecular abnormalities and respond to cognate therapies. For example, BRAFV600E and IDH1/2 mutations; ALK, FGFR, and NTRK fusions; PD-L1 amplification; and CD70 antigens are druggable in both solid and blood malignancies by gene-/immune-targeted therapies/chimeric antigen receptor T cells. Future biomarker-based tissue-agnostic basket studies/approvals should bridge the great divide and include both solid and hematologic cancers.
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Affiliation(s)
- Jacob J Adashek
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD, USA.
| | - Javier L Munoz
- Department of Hematology, Mayo Clinic Arizona, Phoenix, AZ, USA.
| | - Razelle Kurzrock
- Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; WIN Consortium, Paris, France; University of Nebraska, Omaha, NE, USA.
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Mattioda C, Voena C, Ciardelli G, Mattu C. In Vitro 3D Models of Haematological Malignancies: Current Trends and the Road Ahead? Cells 2025; 14:38. [PMID: 39791739 PMCID: PMC11720277 DOI: 10.3390/cells14010038] [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: 11/26/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025] Open
Abstract
Haematological malignancies comprise a diverse group of life-threatening systemic diseases, including leukaemia, lymphoma, and multiple myeloma. Currently available therapies, including chemotherapy, immunotherapy, and CAR-T cells, are often associated with important side effects and with the development of drug resistance and, consequently, disease relapse. In the last decades, it was largely demonstrated that the tumor microenvironment significantly affects cancer cell proliferation and tumor response to treatment. The development of biomimetic, in vitro models may promote the investigation of the interactions between cancer cells and the tumor microenvironment and may help to better understand the mechanisms leading to drug resistance. Although advanced in vitro models have been largely explored in the field of solid tumors, due to the complex nature of the blood cancer tumor microenvironment, the mimicking of haematological malignancies mostly relies on simpler systems, often limited to two-dimensional cell culture, which intrinsically excludes the microenvironmental niche, or to ethically debated animal models. This review aims at reporting an updated overview of state-of-the-art hematological malignancies 3D in vitro models, emphasizing the key features and limitations of existing systems to inspire further research in this underexplored field.
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Affiliation(s)
- Carlotta Mattioda
- DIMEAS, Politecnico di Torino, C.so Duca degli Abruzzi 24, 10129 Torino, Italy; (C.M.); (G.C.)
| | - Claudia Voena
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy;
| | - Gianluca Ciardelli
- DIMEAS, Politecnico di Torino, C.so Duca degli Abruzzi 24, 10129 Torino, Italy; (C.M.); (G.C.)
| | - Clara Mattu
- DIMEAS, Politecnico di Torino, C.so Duca degli Abruzzi 24, 10129 Torino, Italy; (C.M.); (G.C.)
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43
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Stephan P, Perrot J, Voisin A, Barbery M, Andrieu T, Grimont M, Caramel J, Bardou M, Tondeur G, Missiaglia E, Gaulard P, Lemmonier F, De Leval L, Bachy E, Sujobert P, Genestier L, Traverse-Glehen A, Grinberg-Bleyer Y. Deep phenotyping of nodal T-cell lymphomas reveals immune alterations and therapeutic targets. Haematologica 2025; 110:129-141. [PMID: 38813724 PMCID: PMC11694117 DOI: 10.3324/haematol.2023.284448] [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: 10/16/2023] [Accepted: 05/17/2024] [Indexed: 05/31/2024] Open
Abstract
Whereas immunotherapies have revolutionized the treatment of different solid and hematologic cancers, their efficacy in nodal peripheral T-cell lymphomas (PTCL) is limited, due to a lack of understanding of the immune response they trigger. To fully characterize the immune tumor microenvironment (TME) of PTCL, we performed spectral flow cytometry analyses on 11 angioimmunoblastic T-cell lymphomas (AITL), 7 PTCL, not otherwise specified (PTCL, NOS) lymph node samples, and 10 non-tumoral control samples. The PTCL TME contained a larger proportion of regulatory T cells and exhausted CD8+ T cells, with enriched expression of druggable immune checkpoints. Interestingly, CD39 expression was up-regulated at the surface of most immune cells, and a multi-immunofluorescence analysis on a retrospective cohort of 43 AITL patients demonstrated a significant association between high CD39 expression by T cells and poor patient prognosis. Together, our study unravels the complex TME of nodal PTCL, identifies targetable immune checkpoints, and highlights CD39 as a novel prognostic factor.
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MESH Headings
- Humans
- Tumor Microenvironment/immunology
- Immunophenotyping
- Lymphoma, T-Cell, Peripheral/immunology
- Lymphoma, T-Cell, Peripheral/genetics
- Lymphoma, T-Cell, Peripheral/pathology
- Lymphoma, T-Cell, Peripheral/therapy
- Prognosis
- Apyrase/metabolism
- Apyrase/genetics
- Female
- Male
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Middle Aged
- Lymph Nodes/pathology
- Lymph Nodes/immunology
- Biomarkers, Tumor
- Aged
- Retrospective Studies
- Lymphoma, T-Cell/pathology
- Lymphoma, T-Cell/immunology
- Lymphoma, T-Cell/genetics
- Lymphoma, T-Cell/therapy
- Lymphoma, T-Cell/metabolism
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- Antigens, CD/metabolism
- Antigens, CD/genetics
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Affiliation(s)
- Pierre Stephan
- Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Université Claude Bernard Lyon 1, Labex DEV2CAN, Centre Léon Bérard, Lyon
| | - Jimmy Perrot
- Centre Hospitalier Lyon Sud and Université Claude Bernard Lyon-1, Pierre- Bénite
| | - Allison Voisin
- Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Université Claude Bernard Lyon 1, Labex DEV2CAN, Centre Léon Bérard, Lyon
| | - Maud Barbery
- Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Université Claude Bernard Lyon 1, Labex DEV2CAN, Centre Léon Bérard, Lyon
| | - Thibault Andrieu
- Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Université Claude Bernard Lyon 1, Labex DEV2CAN, Centre Léon Bérard, Lyon
| | - Maxime Grimont
- Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Université Claude Bernard Lyon 1, Labex DEV2CAN, Centre Léon Bérard, Lyon
| | - Julie Caramel
- Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Université Claude Bernard Lyon 1, Labex DEV2CAN, Centre Léon Bérard, Lyon
| | - Mathilde Bardou
- Centre Hospitalier Lyon Sud and Université Claude Bernard Lyon-1, Pierre- Bénite
| | - Garance Tondeur
- Centre Hospitalier Lyon Sud and Université Claude Bernard Lyon-1, Pierre- Bénite
| | - Edoardo Missiaglia
- Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Lausanne University, Lausanne
| | - Philippe Gaulard
- AP-HP, Henri Mondor Hospital, Pathology Department, Créteil, France; University Paris Est Créteil, INSERM, IMRB, Créteil
| | - François Lemmonier
- AP-HP, Henri Mondor Hospital, Pathology Department, Créteil, France; University Paris Est Créteil, INSERM, IMRB, Créteil
| | - Laurence De Leval
- Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Lausanne University, Lausanne
| | - Emmanuel Bachy
- Centre Hospitalier Lyon Sud and Université Claude Bernard Lyon-1, Pierre- Bénite, France; Centre International de Recherche en Infectiologie (CIRI), Team Lymphoma Immuno-Biology, UMR INSERM U1111, CNRS 5308, Université Claude Bernard Lyon I, ENS de Lyon, Lyon
| | - Pierre Sujobert
- Centre Hospitalier Lyon Sud and Université Claude Bernard Lyon-1, Pierre- Bénite, France; Centre International de Recherche en Infectiologie (CIRI), Team Lymphoma Immuno-Biology, UMR INSERM U1111, CNRS 5308, Université Claude Bernard Lyon I, ENS de Lyon, Lyon
| | - Laurent Genestier
- Centre International de Recherche en Infectiologie (CIRI), Team Lymphoma Immuno-Biology, UMR INSERM U1111, CNRS 5308, Université Claude Bernard Lyon I, ENS de Lyon, Lyon
| | | | - Yenkel Grinberg-Bleyer
- Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Université Claude Bernard Lyon 1, Labex DEV2CAN, Centre Léon Bérard, Lyon.
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44
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Knittel G, Reinhardt HC. Genetic Mouse Models of Lymphomas. Methods Mol Biol 2025; 2865:411-428. [PMID: 39424735 DOI: 10.1007/978-1-0716-4188-0_18] [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: 10/21/2024]
Abstract
Mouse models are an indispensable tool in lymphoma research. Here, we focus on the utilization of genetically engineered mouse models as preclinical avatars in lymphoma research. We describe lymphoma-relevant alleles and allele combinations, as well as general considerations for model selection. We further illustrate concepts of gene targeting and model design and provide guidelines for breeding strategies and colony maintenance.
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Affiliation(s)
- Gero Knittel
- University Hospital Essen, Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, University of Duisburg-Essen, Essen, Germany.
| | - Hans Christian Reinhardt
- University Hospital Essen, Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, University of Duisburg-Essen, Essen, Germany
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45
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Fukui-Morimoto A, Serizawa K, Fujimoto K, Hanamoto A, Iwata Y, Kakutani H, Kumode T, Hirase C, Morita Y, Tatsumi Y, Hanamoto H, Tanaka H, Matsumura I. CD34 + and CD34 - MM cells show different immune-checkpoint molecule expression profiles: high expression of CD112 and CD137 ligand on CD34 + MM cells. Int J Hematol 2025; 121:89-99. [PMID: 39531203 PMCID: PMC11742359 DOI: 10.1007/s12185-024-03867-0] [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: 10/07/2024] [Revised: 10/30/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024]
Abstract
Despite the introduction of new drugs, multiple myeloma (MM) still remains incurable. We previously reported that CD34+ MM cells, which are clonogenic and self-renewing, are therapy-resistant and persist as a major component of minimal residual disease, expanding during relapse. To investigate the effects of immunotherapies such as immune-checkpoint inhibitors, CAR-T therapy, and bispecific antibodies on CD34+ MM cells, we analyzed immune profiles of both MM cells and T cells from MM patients using microarrays and flow cytometry. Ingenuity pathway analysis revealed 14 out of 289 canonical pathways were more active in CD34+ MM cells compared to CD34- cells, many of which were involved in inflammation and immune responses. Notably, PD-1 signaling-related genes were highly expressed in CD34+ MM cells. Among 10 immune-checkpoint molecules, CD34+ cells more frequently expressed CD112, CD137L, CD270, CD275, and GAL9 than CD34- cells in both newly diagnosed and relapsed/resistant patients. In addition, CD4+ and CD8+ T cells more frequently expressed TIGIT and CD137, suggesting that CD112/TIGIT and CD137L/CD137 interactions may suppress T-cell activity against CD34+ MM cells. Furthermore, our finding of higher FcRH5 expression on CD34+ MM cells is encouraging for future research into the efficacy of FcRH5-targeted therapy in MM.
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Affiliation(s)
- Ayano Fukui-Morimoto
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan
| | - Kentaro Serizawa
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan.
| | - Ko Fujimoto
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan
| | - Aki Hanamoto
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan
| | - Yoshio Iwata
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan
| | - Hiroaki Kakutani
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan
| | - Takahiro Kumode
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan
| | - Chikara Hirase
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan
| | - Yasuyoshi Morita
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan
| | - Yoichi Tatsumi
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan
| | - Hitoshi Hanamoto
- Department of Hematology, Kindai University Nara Hospital, Ikoma, Nara, Japan
| | - Hirokazu Tanaka
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan
| | - Itaru Matsumura
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 5898511, Japan
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46
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Lynch RC, Binkley MS. Rising to the Top: How Immune-Checkpoint Inhibitors are Changing the Landscape of Treatment for Classic Hodgkin Lymphoma. Semin Radiat Oncol 2025; 35:40-46. [PMID: 39672641 DOI: 10.1016/j.semradonc.2024.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2024]
Abstract
Immune checkpoint inhibitors have transformed the future management of classic Hodgkin lymphoma (CHL) in the frontline and salvage settings. Both nivolumab and pembrolizumab have high efficacy in CHL allowing for reduction of chemotherapy and possibly the use of radiotherapy based on short-term follow-up. In this review article, we highlight recent trials enrolling patients with relapse and refractory classic Hodgkin lymphoma receiving monotherapy with PD-1 inhibitors as well as PD-1 and chemotherapy regimens. We also highlight frontline trials utilizing PD-1 inhibitors with chemotherapy with or without radiotherapy. Collectively, the role for radiotherapy in the frontline or salvage setting will become more defined with long-term follow-up of completed studies and results generated from future studies.
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Affiliation(s)
- Ryan C Lynch
- Division of Hematology/Oncology, University of Washington, Seattle, WA.
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47
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Huang Y, Chen Z, Shen G, Fang S, Zheng J, Chi Z, Zhang Y, Zou Y, Gan Q, Liao C, Yao Y, Kong J, Fan X. Immune regulation and the tumor microenvironment in anti-PD-1/PDL-1 and anti-CTLA-4 therapies for cancer immune evasion: A bibliometric analysis. Hum Vaccin Immunother 2024; 20:2318815. [PMID: 38419524 PMCID: PMC11789735 DOI: 10.1080/21645515.2024.2318815] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/26/2024] [Accepted: 02/11/2024] [Indexed: 03/02/2024] Open
Abstract
This study aims to conduct a bibliometric analysis, employing visualization tools to examine literature pertaining to tumor immune evasion related to anti-CTLA-4 and anti-PD-1/PD-L1 therapy from 1999 to 2022. A special emphasis is placed on the interplay between tumor microenvironment, signaling pathways, immune cells and immune evasion, with data sourced from the Web of Science core collection (WoSCC). Advanced tools, including VOSviewer, Citespace, and Scimago Graphica, were utilized to analyze various parameters, such as co-authorship/co-citation patterns, regional contributions, journal preferences, keyword co-occurrences, and significant citation bursts. Out of 4778 publications reviewed, there was a marked increase in research focusing on immune evasion, with bladder cancer being notably prominent. Geographically, China, the USA, and Japan were the leading contributors. Prestigious institutions like MD Anderson Cancer Center, Harvard Medical School, Fudan University, and Sun Yat Sen University emerged as major players. Renowned journals in this domain included Frontiers in Immunology, Cancers, and Frontiers in Oncology. Ehen LP and Wang W were identified as prolific authors on this topic, while Topalian SL stood out as one of the most cited. Research current situation is notably pivoting toward challenges like immunotherapy resistance and the intricate signaling pathways driving drug resistance. This bibliometric study seeks to provide a comprehensive overview of past and current research trends, emphasizing the potential role of tumor microenvironment, signaling pathways and immune cells in the context of immune checkpoint inhibitors (ICIs) and tumor immune evasion.
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Affiliation(s)
- Yi Huang
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Zhijian Chen
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Gang Shen
- Department of Urology, DUSHU Lake Hospital Affiliated to Soochow University, Suzhou, China
| | - Shuogui Fang
- Department of Radiotherapy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China
| | - Junjiong Zheng
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Zepai Chi
- Department of urology, Shantou Central Hospital, Shantou, China
| | - Yuanfeng Zhang
- Department of urology, Shantou Central Hospital, Shantou, China
| | - Yitong Zou
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Qinghua Gan
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Chengxiao Liao
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Yuhui Yao
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Jianqiu Kong
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Xinxiang Fan
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen University, Guangzhou, P. R. China
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48
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Paczkowska J, Tang M, Wright KT, Song L, Luu K, Shanmugam V, Welsh EL, Weirather JL, Besson N, Olszewski H, Porter BA, Pfaff KL, Redd RA, Cader FZ, Mandato E, Ouyang J, Calabretta E, Bai G, Lawton LN, Armand P, Rodig SJ, Liu XS, Shipp MA. Cancer-specific innate and adaptive immune rewiring drives resistance to PD-1 blockade in classic Hodgkin lymphoma. Nat Commun 2024; 15:10740. [PMID: 39737927 PMCID: PMC11686379 DOI: 10.1038/s41467-024-54512-7] [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: 02/07/2024] [Accepted: 11/11/2024] [Indexed: 01/01/2025] Open
Abstract
Hodgkin Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma (cHL), like many solid tumors, elicit ineffective immune responses. However, patients with cHL are highly responsive to PD-1 blockade, which largely depends on HRS cell-specific retention of MHC class II and implicates CD4+ T cells and additional MHC class I-independent immune effectors. Here, we utilize single-cell RNA sequencing and spatial analysis to define shared circulating and microenvironmental features of the immune response to PD-1 blockade in cHL. Compared with non-responders, responding patients have more circulating CD4+ naïve and central memory T cells and B cells, as well as more diverse CD4+ T cell and B cell receptor repertoires. Importantly, a population of circulating and tumor-infiltrating IL1β+ monocytes/macrophages is detectable in patients with cHL but not healthy donors, and a proinflammatory, tumor-promoting signature of these circulating IL1β+ monocytes is associated with resistance to PD-1 blockade in cHL. Altogether, our findings reveal extensive immune rewiring and complementary roles of CD4+ T cells, B cells and IL1β+ monocytes in the response to PD-1 blockade and suggest that these features can be captured with a peripheral blood test.
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Affiliation(s)
- Julia Paczkowska
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ming Tang
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
- Astra Zeneca, Waltham, MA, USA
| | - Kyle T Wright
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Li Song
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biomedical Data Science, Dartmouth College, Hanover, NH, USA
| | - Kelsey Luu
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
- PathAI, Boston, MA, USA
| | - Vignesh Shanmugam
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Emma L Welsh
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jason L Weirather
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Naomi Besson
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Harrison Olszewski
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Billie A Porter
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Kathleen L Pfaff
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Robert A Redd
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Fathima Zumla Cader
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- AstraZeneca, City House, Cambridge, UK
| | - Elisa Mandato
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jing Ouyang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Mechanisms of Cancer Resistance Thematic Center, Bristol Myers Squibb, Cambridge, MA, USA
| | - Eleonora Calabretta
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Gali Bai
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA
| | - Lee N Lawton
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Philippe Armand
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Scott J Rodig
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Xiaole Shirley Liu
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard T.H. Chan School of Public Health, Boston, MA, USA
- GV20 Therapeutics, LLC, Cambridge, MA, USA
| | - Margaret A Shipp
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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49
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Hosseininejad-Chafi M, Eftekhari Z, Oghalaie A, Behdani M, Sotoudeh N, Kazemi-Lomedasht F. Nanobodies as innovative immune checkpoint modulators: advancing cancer immunotherapy. Med Oncol 2024; 42:36. [PMID: 39719469 DOI: 10.1007/s12032-024-02588-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 12/14/2024] [Indexed: 12/26/2024]
Abstract
The immune system relies on a delicate balance between attacking harmful pathogens and preserving the body's own tissues, a balance maintained by immune checkpoints. These checkpoints play a critical role in preventing autoimmune diseases by restraining excessive immune responses while allowing the immune system to recognize and destroy abnormal cells, such as tumors. In recent years, immune checkpoint inhibitors (ICIs) have become central to cancer therapy, enabling the immune system to target and eliminate cancer cells that evade detection. Traditional antibodies, such as IgGs, have been widely used in immune therapies but are limited by their size and complexity. Nanobodies (Nbs), derived from camelid heavy-chain-only antibodies, offer a promising alternative. These small, stable antibody fragments retain the antigen-binding specificity of traditional antibodies but have enhanced solubility and the ability to target otherwise inaccessible epitopes. This review explores the use of Nbs as ICIs, emphasizing their potential in cancer immunotherapy and other immune-related treatments. Their unique structural properties and small size make Nbs highly effective tools for modulating immune responses, representing a novel approach in the evolving landscape of checkpoint inhibitor therapies.
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Affiliation(s)
- Mohammad Hosseininejad-Chafi
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Zohre Eftekhari
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Akbar Oghalaie
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Mahdi Behdani
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Nazli Sotoudeh
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran
| | - Fatemeh Kazemi-Lomedasht
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, 1316943551, Iran.
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50
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Roschewski M, Phelan JD, Jaffe ES. Primary large B-cell lymphomas of immune-privileged sites. Blood 2024; 144:2593-2603. [PMID: 38635786 PMCID: PMC11862818 DOI: 10.1182/blood.2023020911] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/22/2024] [Accepted: 04/02/2024] [Indexed: 04/20/2024] Open
Abstract
ABSTRACT Diffuse large B-cell lymphoma (DLBCL) encompasses a diverse spectrum of aggressive B-cell lymphomas with remarkable genetic heterogeneity and myriad clinical presentations. Multiplatform genomic analyses of DLBCL have identified oncogenic drivers within genetic subtypes that allow for pathologic subclassification of tumors into discrete entities with shared immunophenotypic, genetic, and clinical features. Robust classification of lymphoid tumors establishes a foundation for precision medicine and enables the identification of novel therapeutic vulnerabilities within biologically homogeneous entities. Most cases of DLBCL involving the central nervous system (CNS), vitreous, and testis exhibit immunophenotypic features suggesting an activated B-cell (ABC) origin. Shared molecular features include frequent comutations of MYD88 (L265P) and CD79B and frequent genetic alterations promoting immune evasion, which are hallmarks of the MCD/C5/MYD88 genetic subtype of DLBCL. Clinically, these lymphomas primarily arise within anatomic sanctuary sites and have a predilection for remaining confined to extranodal sites and strong CNS tropism. Given the shared clinical and molecular features, the umbrella term primary large B-cell lymphoma of immune-privileged sites (IP-LBCL) was proposed. Other extranodal DLBCL involving the breast, adrenal glands, and skin are often ABC DLBCL but are more heterogeneous in their genomic profile and involve anatomic sites that are not considered immune privileged. In this review, we describe the overlapping clinical, pathologic, and molecular features of IP-LBCL and highlight important considerations for diagnosis, staging, and treatment. We also discuss potential therapeutic vulnerabilities of IP-LBCL including sensitivity to inhibitors of Bruton tyrosine kinase, immunomodulatory agents, and immunotherapy.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/classification
- Lymphoma, Large B-Cell, Diffuse/diagnosis
- Immune Privilege
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Affiliation(s)
- Mark Roschewski
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - James D. Phelan
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Elaine S. Jaffe
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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