1
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Chiu DKC, Zhang X, Cheng BYL, Liu Q, Hayashi K, Yu B, Lee R, Zhang C, An X, Rajadas J, Reticker-Flynn NE, Rankin EB, Engleman EG. Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity. Science 2025; 388:eadr3026. [PMID: 40273234 DOI: 10.1126/science.adr3026] [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: 06/25/2024] [Revised: 12/20/2024] [Accepted: 03/05/2025] [Indexed: 04/26/2025]
Abstract
Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell-rich or a noninflamed T cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.
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Affiliation(s)
| | - Xiangyue Zhang
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Bowie Yik-Ling Cheng
- Stanford Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA
| | - Qiang Liu
- Advanced Drug Delivery and Regenerative Biomaterials Laboratory, Cardiovascular Institute, Department of Medicine, Stanford University, Stanford, CA, USA
| | | | - Bo Yu
- ImmunEdge Inc., Mountain View, CA, USA
| | - Ryan Lee
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Catherine Zhang
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Xiuli An
- Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA
| | - Jayakumar Rajadas
- Advanced Drug Delivery and Regenerative Biomaterials Laboratory, Cardiovascular Institute, Department of Medicine, Stanford University, Stanford, CA, USA
| | | | - Erinn B Rankin
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University, Palo Alto, CA, USA
| | - Edgar G Engleman
- Department of Pathology, Stanford University, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University, Palo Alto, CA, USA
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2
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Kumagai S, Momoi Y, Nishikawa H. Immunogenomic cancer evolution: A framework to understand cancer immunosuppression. Sci Immunol 2025; 10:eabo5570. [PMID: 40153489 DOI: 10.1126/sciimmunol.abo5570] [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: 08/29/2022] [Revised: 06/26/2024] [Accepted: 03/05/2025] [Indexed: 03/30/2025]
Abstract
The process of tumor development involves tumor cells eluding detection and suppression of immune responses, which can cause decreased tumor cell antigenicity, expression of immunosuppressive molecules, and immunosuppressive cell recruitment to the tumor microenvironment (TME). Immunologically and genomically integrated analysis (immunogenomic analysis) of patient specimens has revealed that oncogenic aberrant signaling is involved in both carcinogenesis and immune evasion. In noninflamed cancers such as epidermal growth factor receptor (EGFR)-mutated lung cancers, genetic abnormalities in cancer cells contribute to the formation of an immunosuppressive TME by recruiting immunosuppressive cells, which cannot be fully explained by the cancer immunoediting hypothesis. This review summarizes the latest findings regarding the links between cancer genetic abnormalities and immunosuppression causing clinical resistance to immunotherapy. We propose the concepts of immunogenomic cancer evolution, in which cancer cell genomic evolution shapes the immunosuppressive TME, and immunogenomic precision medicine, in which cancer immunotherapy can be combined with molecularly targeted reagents that modulate the immunosuppressive TME.
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Affiliation(s)
- Shogo Kumagai
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
- Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba 277-8577, Japan
- Division of Cellular Signaling, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
| | - Yusaku Momoi
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
- Department of Tumor Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
- Division of Cancer Immune Multicellular System Regulation, Center for Cancer Immunotherapy and Immunology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
- Kindai University Faculty of Medicine, Osaka-sayama 589-8511, Japan
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3
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Ofner H, Kramer G, Shariat SF, Hassler MR. TP53 Deficiency in the Natural History of Prostate Cancer. Cancers (Basel) 2025; 17:645. [PMID: 40002239 PMCID: PMC11853097 DOI: 10.3390/cancers17040645] [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: 12/24/2024] [Revised: 02/01/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
Prostate cancer remains a leading cause of cancer-related mortality in men, with advanced stages posing significant treatment challenges due to high morbidity and mortality. Among genetic alterations, TP53 mutations are among the most prevalent in cancers and are strongly associated with poor clinical outcomes and therapeutic resistance. This review investigates the role of TP53 mutations in prostate cancer progression, prognosis, and therapeutic development. A comprehensive analysis of preclinical and clinical studies was conducted to elucidate the molecular mechanisms, clinical implications, and potential therapeutic approaches associated with TP53 alterations in prostate cancer. TP53 mutations are highly prevalent in advanced stages, contributing to genomic instability, aggressive tumor phenotypes, and resistance to standard treatments. Emerging evidence supports the utility of liquid biopsy techniques, such as circulating tumor DNA analysis, for detecting TP53 mutations, providing prognostic value and facilitating early intervention strategies. Novel therapeutic approaches targeting TP53 have shown promise in preclinical settings, but their clinical efficacy requires further validation. Overall, TP53 mutations represent a critical biomarker for disease progression and therapeutic response in prostate cancer. Advances in detection methods and targeted therapies hold significant potential to improve outcomes for patients with TP53-mutated prostate cancer. Further research is essential to integrate TP53-based strategies into routine clinical practice.
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Affiliation(s)
- Heidemarie Ofner
- Department of Urology, Medical University of Vienna, 1090 Vienna, Austria; (H.O.); (G.K.); (S.F.S.)
| | - Gero Kramer
- Department of Urology, Medical University of Vienna, 1090 Vienna, Austria; (H.O.); (G.K.); (S.F.S.)
| | - Shahrokh F. Shariat
- Department of Urology, Medical University of Vienna, 1090 Vienna, Austria; (H.O.); (G.K.); (S.F.S.)
- Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman 19328, Jordan
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Urology, Second Faculty of Medicine, Charles University, 150 06 Prague, Czech Republic
- Department of Urology, Weill Cornell Medical College, New York, NY 10065, USA
- Karl Landsteiner Institute of Urology and Andrology, 1090 Vienna, Austria
| | - Melanie R. Hassler
- Department of Urology, Medical University of Vienna, 1090 Vienna, Austria; (H.O.); (G.K.); (S.F.S.)
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4
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Brea L, Yu J. Tumor-intrinsic regulators of the immune-cold microenvironment of prostate cancer. Trends Endocrinol Metab 2025:S1043-2760(24)00325-4. [PMID: 39753502 DOI: 10.1016/j.tem.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 01/24/2025]
Abstract
Prostate cancer (PC) is a notoriously immune-cold tumor in that it often lacks substantial infiltration by antitumor immune cells, and in advanced diseases such as neuroendocrine PC, it could be devoid of immune cells. A majority of PC patients thus have, unfortunately, been unable to benefit from recent advances in immunotherapies. What causes this immunosuppressive microenvironment around PC? In this review, we discuss various genetic and epigenetic regulators intrinsic to prostate tumor cells that could have profound effects on the tumor microenvironment, thus contributing to this immune-cold status. It will be essential to target the cancer cells themselves in order to change the tumor microenvironment to harness existing and developing immunotherapies that had great success in other tumors.
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Affiliation(s)
- Lourdes Brea
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA; Division of Hematology/Oncology, Department of Medicine, Northwestern University, Chicago, IL, USA
| | - Jindan Yu
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
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5
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Hanahan D, Michielin O, Pittet MJ. Convergent inducers and effectors of T cell paralysis in the tumour microenvironment. Nat Rev Cancer 2025; 25:41-58. [PMID: 39448877 DOI: 10.1038/s41568-024-00761-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2024] [Indexed: 10/26/2024]
Abstract
Tumorigenesis embodies the formation of a heterotypic tumour microenvironment (TME) that, among its many functions, enables the evasion of T cell-mediated immune responses. Remarkably, most TME cell types, including cancer cells, fibroblasts, myeloid cells, vascular endothelial cells and pericytes, can be stimulated to deploy immunoregulatory programmes. These programmes involve regulatory inducers (signals-in) and functional effectors (signals-out) that impair CD8+ and CD4+ T cell activity through cytokines, growth factors, immune checkpoints and metabolites. Some signals target specific cell types, whereas others, such as transforming growth factor-β (TGFβ) and prostaglandin E2 (PGE2), exert broad, pleiotropic effects; as signals-in, they trigger immunosuppressive programmes in most TME cell types, and as signals-out, they directly inhibit T cells and also modulate other cells to reinforce immunosuppression. This functional diversity and redundancy pose a challenge for therapeutic targeting of the immune-evasive TME. Fundamentally, the commonality of regulatory programmes aimed at abrogating T cell activity, along with paracrine signalling between cells of the TME, suggests that many normal cell types are hard-wired with latent functions that can be triggered to prevent inappropriate immune attack. This intrinsic capability is evidently co-opted throughout the TME, enabling tumours to evade immune destruction.
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Affiliation(s)
- Douglas Hanahan
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
- Agora Cancer Research Center, Lausanne, Switzerland.
- Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland.
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
| | - Olivier Michielin
- Agora Cancer Research Center, Lausanne, Switzerland
- Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland
- Department of Oncology, Geneva University Hospitals (HUG), Geneva, Switzerland
- Department of Medicine, University of Geneva (UNIGE), Geneva, Switzerland
| | - Mikael J Pittet
- Agora Cancer Research Center, Lausanne, Switzerland
- Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
- Department of Oncology, Geneva University Hospitals (HUG), Geneva, Switzerland
- Department of Pathology and Immunology, University of Geneva (UNIGE), Geneva, Switzerland
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6
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Wang X, Yang J, Yang W, Sheng H, Jia B, Cheng P, Xu S, Hong X, Jiang C, Yang Y, Wu Z, Wang J. Multiple roles of p53 in cancer development: Regulation of tumor microenvironment, m 6A modification and diverse cell death mechanisms. J Adv Res 2024:S2090-1232(24)00481-8. [PMID: 39490612 DOI: 10.1016/j.jare.2024.10.026] [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: 07/16/2024] [Revised: 10/02/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND The protein p53, encoded by the most frequently mutated gene TP53 in human cancers, has diverse functions in tumor suppression. As a best known transcription factor, p53 can regulate various fundamental cellular responses, ranging from the cell-cycle arrest, DNA repair, senescence to the programmed cell death (PCD), which includes autophagy, apoptosis, ferroptosis, cuproptosis, pyroptosis and disulfidoptosis. Accumulating evidence has indicated that the tumor microenvironment (TME), N6-methyladenosine (m6A) modification and diverse PCD are important for the progression, proliferation and metastases of cancers. AIM OF REVIEW This paper aims to systematically and comprehensively summarize the multiple roles of p53 in the development of cancers from the regulation of TME, m6A Modification and diverse PCD. KEY SCIENTIFIC CONCEPTS OF REVIEW TME, a crucial local homeostasis environment, influences every step of tumorigenesis and metastasis. m6A, the most prevalent and abundant endogenous modification in eukaryotic RNAs, plays an essential role in various biological processes, containing the progression of cancers. Additionally, PCD is an evolutionarily conserved mechanism of cell suicide and a common process in living organisms. Some forms of PCD contribute to the occurrence and development of cancer. However, the complex roles of p53 within the TME, m6A modification and diverse PCD mechanisms are still not completely understood. Presently, the function roles of p53 including the wild-type and mutant p53 in different context are summarized. Additionally, the interaction between the cancer immunity, cancer cell death and RNA m6A methylation and the p53 regulation during the development and progress of cancers were discussed. Moreover, the key molecular mechanisms by which p53 participates in the regulation of TME, m6A and diverse PCD are also explored. All the findings will facilitate the development of novel therapeutic approaches.
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Affiliation(s)
- Xiangyu Wang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Jianhua Yang
- School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Wanting Yang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Haiyang Sheng
- Global Biometrics and Data Sciences, Bristol Myers Squibb, New York City, USA
| | - Buyun Jia
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Peng Cheng
- The First Affiliated Hospital, Anhui University of Traditional Chinese Medicine, Hefei, Anhui, China
| | - Shanshan Xu
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Xinhui Hong
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Chuanwei Jiang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Yinfeng Yang
- School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, Anhui, China.
| | - Ziyin Wu
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Jiangsu Kanion Pharmaceutical Co. Ltd, Lianyungang, Jiangsu, China.
| | - Jinghui Wang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China.
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7
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Unal B, Kuzu OF, Jin Y, Osorio D, Kildal W, Pradhan M, Kung SHY, Oo HZ, Daugaard M, Vendelbo M, Patterson JB, Thomsen MK, Kuijjer ML, Saatcioglu F. Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer. Nat Commun 2024; 15:8895. [PMID: 39406723 PMCID: PMC11480464 DOI: 10.1038/s41467-024-53039-1] [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: 07/20/2023] [Accepted: 09/30/2024] [Indexed: 10/19/2024] Open
Abstract
Unfolded protein response (UPR) is a central stress response pathway that is hijacked by tumor cells for their survival. Here, we find that IRE1α signaling, one of the canonical UPR arms, is increased in prostate cancer (PCa) patient tumors. Genetic or small molecule inhibition of IRE1α in syngeneic mouse PCa models and an orthotopic model decreases tumor growth. IRE1α ablation in cancer cells potentiates interferon responses and activates immune system related pathways in the tumor microenvironment (TME). Single-cell RNA-sequencing analysis reveals that targeting IRE1α in cancer cells reduces tumor-associated macrophage abundance. Consistently, the small molecule IRE1α inhibitor MKC8866, currently in clinical trials, reprograms the TME and enhances anti-PD-1 therapy. Our findings show that IRE1α signaling not only promotes cancer cell growth and survival but also interferes with anti-tumor immunity in the TME. Thus, targeting IRE1α can be a promising approach for improving anti-PD-1 immunotherapy in PCa.
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Affiliation(s)
- Bilal Unal
- Department of Biosciences, University of Oslo, Oslo, Norway
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
| | - Omer Faruk Kuzu
- Department of Biosciences, University of Oslo, Oslo, Norway
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
| | - Yang Jin
- Department of Biosciences, University of Oslo, Oslo, Norway
| | - Daniel Osorio
- Center for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway
| | - Wanja Kildal
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
| | - Manohar Pradhan
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
| | - Sonia H Y Kung
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - Htoo Zarni Oo
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - Mads Daugaard
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - Mikkel Vendelbo
- Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | | | | | - Marieke Lydia Kuijjer
- Center for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
- Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | - Fahri Saatcioglu
- Department of Biosciences, University of Oslo, Oslo, Norway.
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.
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8
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Galey L, Olanrewaju A, Nabi H, Paquette JS, Pouliot F, Audet-Walsh É. PSA, an outdated biomarker for prostate cancer: In search of a more specific biomarker, citrate takes the spotlight. J Steroid Biochem Mol Biol 2024; 243:106588. [PMID: 39025336 DOI: 10.1016/j.jsbmb.2024.106588] [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: 05/15/2024] [Revised: 07/12/2024] [Accepted: 07/14/2024] [Indexed: 07/20/2024]
Abstract
The prevailing biomarker employed for prostate cancer (PCa) screening and diagnosis is the prostate-specific antigen (PSA). Despite excellent sensitivity, PSA lacks specificity, leading to false positives, unnecessary biopsies and overdiagnosis. Consequently, PSA is increasingly less used by clinicians, thus underscoring the imperative for the identification of new biomarkers. An emerging biomarker in this context is citrate, a molecule secreted by the normal prostate, which has been shown to be inversely correlated with PCa. Here, we discuss about PSA and its usage for PCa diagnosis, its lack of specificity, and the various conditions that can affect its levels. We then provide our vision about what we think would be a valuable addition to our PCa diagnosis toolkit, citrate. We describe the unique citrate metabolic program in the prostate and how this profile is reprogrammed during carcinogenesis. Finally, we summarize the evidence that supports the usage of citrate as a biomarker for PCa diagnosis, as it can be measured in various patient samples and be analyzed by several methods. The unique relationship between citrate and PCa, combined with the stability of citrate levels in other prostate-related conditions and the simplicity of its detection, further accentuates its potential as a biomarker.
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Affiliation(s)
- Lucas Galey
- Endocrinology - Nephrology Research Axis, Centre de recherche du CHU de Québec - Université Laval, Québec City, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec City, Canada; Centre de recherche sur le cancer de l'Université Laval, Québec City, Canada
| | - Ayokunle Olanrewaju
- Department of Mechanical Engineering, University of Washington, Seattle, WA, USA; Department of Bioengineering, University of Washington, Seattle, WA, USA
| | - Hermann Nabi
- Centre de recherche sur le cancer de l'Université Laval, Québec City, Canada
| | - Jean-Sébastien Paquette
- Laboratoire de recherche et d'innovation en médecine de première ligne (ARIMED), Groupe de médecine de famille universitaire de Saint-Charles-Borromée, CISSS Lanaudière, Saint-Charles-Borromée, QC, Canada; VITAM Research Centre for Sustainable Health, Québec, QC, Canada; Department of Family Medicine and Emergency Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada
| | - Frédéric Pouliot
- Centre de recherche sur le cancer de l'Université Laval, Québec City, Canada; Department of Family Medicine and Emergency Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada; Department of surgery, Faculty of Medicine, Université Laval, Québec, QC, Canada
| | - Étienne Audet-Walsh
- Endocrinology - Nephrology Research Axis, Centre de recherche du CHU de Québec - Université Laval, Québec City, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec City, Canada; Centre de recherche sur le cancer de l'Université Laval, Québec City, Canada.
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9
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Lu J, Huo W, Ma Y, Wang X, Yu J. Suppressive immune microenvironment and CART therapy for glioblastoma: Future prospects and challenges. Cancer Lett 2024; 600:217185. [PMID: 39142498 DOI: 10.1016/j.canlet.2024.217185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 08/16/2024]
Abstract
Glioblastoma, a highly malignant intracranial tumor, has acquired slow progress in treatment. Previous clinical trials involving targeted therapy and immune checkpoint inhibitors have shown no significant benefits in treating glioblastoma. This ineffectiveness is largely due to the complex immunosuppressive environment of glioblastoma. Glioblastoma cells exhibit low immunogenicity and strong heterogeneity and the immune microenvironment is replete with inhibitory cytokines, numerous immunosuppressive cells, and insufficient effective T cells. Fortunately, recent Phase I clinical trials of CART therapy for glioblastoma have confirmed its safety, with a small subset of patients achieving survival benefits. However, CART therapy continues to face challenges, including blood-brain barrier obstruction, antigen loss, and an immunosuppressive tumor microenvironment (TME). This article provides a detailed examination of glioblastoma's immune microenvironment, both from intrinsic and extrinsic tumor cell factors, reviews current clinical and basic research on multi-targets CART treatment, and concludes by outlining the key challenges in using CART cells for glioblastoma therapy.
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Affiliation(s)
- Jie Lu
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Wen Huo
- Department of Radiation Oncology, Affiliated Tumor Hospital of Xinjiang Medical University, China
| | - Yingze Ma
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China; Department of Radiation Oncology, Shandong University Cancer Center, Jinan, Shandong, China
| | - Xin Wang
- Department of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.
| | - Jinming Yu
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China; Research Unit of Radiation Oncology, Chinese Academy of Medical Sciences, Jinan, Shandong, China.
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10
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Zhang W, Lee A, Tiwari AK, Yang MQ. Characterizing the Tumor Microenvironment and Its Prognostic Impact in Breast Cancer. Cells 2024; 13:1518. [PMID: 39329702 PMCID: PMC11429566 DOI: 10.3390/cells13181518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 08/21/2024] [Accepted: 08/27/2024] [Indexed: 09/28/2024] Open
Abstract
The tumor microenvironment (TME) is crucial in cancer development and therapeutic response. Immunotherapy is increasingly recognized as a critical component of cancer treatment. While immunotherapies have shown efficacy in various cancers, including breast cancer, patient responses vary widely. Some patients receive significant benefits, while others experience minimal or no improvement. This disparity underscores the complexity and diversity of the immune system. In this study, we investigated the immune landscape and cell-cell communication within the TME of breast cancer through integrated analysis of bulk and single-cell RNA sequencing data. We established profiles of tumor immune infiltration that span across a broad spectrum of adaptive and innate immune cells. Our clustering analysis of immune infiltration identified three distinct patient groups: high T cell abundance, moderate infiltration, and low infiltration. Patients with low immune infiltration exhibited the poorest survival rates, while those in the moderate infiltration group showed better outcomes than those with high T cell abundance. Moreover, the high cell abundance group was associated with a greater tumor burden and higher rates of TP53 mutations, whereas the moderate infiltration group was characterized by a lower tumor burden and elevated PIK3CA mutations. Analysis of an independent single-cell RNA-seq breast cancer dataset confirmed the presence of similar infiltration patterns. Further investigation into ligand-receptor interactions within the TME unveiled significant variations in cell-cell communication patterns among these groups. Notably, we found that the signaling pathways SPP1 and EGF were exclusively active in the low immune infiltration group, suggesting their involvement in immune suppression. This work comprehensively characterizes the composition and dynamic interplay in the breast cancer TME. Our findings reveal associations between the extent of immune infiltration and clinical outcomes, providing valuable prognostic information for patient stratification. The unique mutations and signaling pathways associated with different patient groups offer insights into the mechanisms underlying diverse tumor immune infiltration and the formation of an immunosuppressive tumor microenvironment.
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Affiliation(s)
- Wenjuan Zhang
- MidSouth Bioinformatics Center and Joint Bioinformatics Graduate Program, University of Arkansas for Medical Sciences, Little Rock, AR 72204, USA
| | - Alex Lee
- Biology Department, University of Arkansas at Little Rock, Little Rock, AR 72204, USA
| | - Amit K. Tiwari
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Mary Qu Yang
- MidSouth Bioinformatics Center and Joint Bioinformatics Graduate Program, University of Arkansas for Medical Sciences, Little Rock, AR 72204, USA
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11
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Liang P, Peng M, Tao J, Wang B, Wei J, Lin L, Cheng B, Xiong S, Li J, Li C, Yu Z, Li C, Wang J, Li H, Chen Z, Fan J, Liang W, He J. Development of a genome atlas for discriminating benign, preinvasive, and invasive lung nodules. MedComm (Beijing) 2024; 5:e644. [PMID: 39036344 PMCID: PMC11258453 DOI: 10.1002/mco2.644] [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: 12/26/2023] [Revised: 06/10/2024] [Accepted: 06/12/2024] [Indexed: 07/23/2024] Open
Abstract
To tackle misdiagnosis in lung cancer screening with low-dose computed tomography (LDCT), we aimed to compile a genome atlas for differentiating benign, preinvasive, and invasive lung nodules and characterize their molecular pathogenesis. We collected 432 lung nodule tissue samples from Chinese patients, spanning benign, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA). We performed comprehensive sequencing, examining somatic variants, gene expressions, and methylation levels. Our findings uncovered EGFR and TP53 mutations as key drivers in - early lung cancer development, with EGFR mutation frequency increasing with disease progression. Both EGFR mutations and EGF/EGFR hypo-methylation activated the EGFR pathway, fueling cancer growth. Transcriptome analysis identified four lung nodule subtypes (G1-4) with distinct molecular features and immune cell infiltrations: EGFR-driven G1, EGFR/TP53 co-mutation G2, inflamed G3, stem-like G4. Estrogen/androgen response was associated with the EGFR pathway, proposing a new therapy combining tyrosine kinase inhibitors with antiestrogens. Preinvasive nodules exhibited stem cell pathway enrichment, potentially hindering invasion. Epigenetic regulation of various genes was essential for lung cancer initiation and development. This study provides insights into the molecular mechanism of neoplastic progression and identifies potential diagnostic biomarkers and therapeutic targets for lung cancer.
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Affiliation(s)
- Peng Liang
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory DiseaseGuangzhouGuangdongChina
| | - Minhua Peng
- AnchorDx Medical Co., LtdGuangzhouGuangdongChina
| | - Jinsheng Tao
- AnchorDx Medical Co., LtdGuangzhouGuangdongChina
| | - Bo Wang
- AnchorDx Medical Co., LtdGuangzhouGuangdongChina
| | - Jinwang Wei
- Department of Data ScienceGenomicare Biotechnology (Shanghai) Co., Ltd.ShanghaiChina
- Department of Data ScienceShanghai CreateCured Biotechnology Co., Ltd.ShanghaiChina
| | - Lixuan Lin
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory DiseaseGuangzhouGuangdongChina
| | - Bo Cheng
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory DiseaseGuangzhouGuangdongChina
| | - Shan Xiong
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory DiseaseGuangzhouGuangdongChina
| | - Jianfu Li
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory DiseaseGuangzhouGuangdongChina
| | - Caichen Li
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory DiseaseGuangzhouGuangdongChina
| | - Ziwen Yu
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory DiseaseGuangzhouGuangdongChina
| | - Chunyan Li
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory DiseaseGuangzhouGuangdongChina
| | - Jun Wang
- AnchorDx Medical Co., LtdGuangzhouGuangdongChina
| | - Hui Li
- AnchorDx Medical Co., LtdGuangzhouGuangdongChina
| | - Zhiwei Chen
- AnchorDx Medical Co., LtdGuangzhouGuangdongChina
- AnchorDx Inc.FremontCaliforniaUSA
| | - Jian‐Bing Fan
- AnchorDx Medical Co., LtdGuangzhouGuangdongChina
- Department of PathologySouthern Medical UniversityGuangzhouGuangdongChina
| | - Wenhua Liang
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory DiseaseGuangzhouGuangdongChina
| | - Jianxing He
- Department of Thoracic Surgery and Oncologythe First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory DiseaseGuangzhouGuangdongChina
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12
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Zahraeifard S, Xiao Z, So JY, Ahad A, Montoya S, Park WY, Sornapudi T, Andohkow T, Read A, Kedei N, Koparde V, Yang H, Lee M, Wong N, Cam M, Wang K, Ruppin E, Luo J, Hollander C, Yang L. Loss of tumor suppressors promotes inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression. Nat Commun 2024; 15:5873. [PMID: 38997291 PMCID: PMC11245525 DOI: 10.1038/s41467-024-50262-8] [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: 03/27/2023] [Accepted: 07/02/2024] [Indexed: 07/14/2024] Open
Abstract
Low response rate, treatment relapse, and resistance remain key challenges for cancer treatment with immune checkpoint blockade (ICB). Here we report that loss of specific tumor suppressors (TS) induces an inflammatory response and promotes an immune suppressive tumor microenvironment. Importantly, low expression of these TSs is associated with a higher expression of immune checkpoint inhibitory mediators. Here we identify, by using in vivo CRISPR/Cas9 based loss-of-function screening, that NF1, TSC1, and TGF-β RII as TSs regulating immune composition. Loss of each of these three TSs leads to alterations in chromatin accessibility and enhances IL6-JAK3-STAT3/6 inflammatory pathways. This results in an immune suppressive landscape, characterized by increased numbers of LAG3+ CD8 and CD4 T cells. ICB targeting LAG3 and PD-L1 simultaneously inhibits metastatic progression in preclinical triple negative breast cancer (TNBC) mouse models of NF1-, TSC1- or TGF-β RII- deficient tumors. Our study thus reveals a role of TSs in regulating metastasis via non-cell-autonomous modulation of the immune compartment and provides proof-of-principle for ICB targeting LAG3 for patients with NF1-, TSC1- or TGF-β RII-inactivated cancers.
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Affiliation(s)
- Sara Zahraeifard
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Zhiguang Xiao
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jae Young So
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Abdul Ahad
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Selina Montoya
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Woo Yong Park
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Trinadharao Sornapudi
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tiffany Andohkow
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Abigail Read
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Noemi Kedei
- Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Vishal Koparde
- Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
- Advanced Biomedical Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA
| | - Howard Yang
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Maxwell Lee
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Nathan Wong
- Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
- Advanced Biomedical Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA
| | - Maggie Cam
- Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Kun Wang
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Eytan Ruppin
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ji Luo
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Christine Hollander
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Li Yang
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
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13
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Abdulrahman Z, Kortekaas KE, Welters MJP, van Poelgeest MIE, van der Burg SH. Monocyte infiltration is an independent positive prognostic biomarker in vulvar squamous cell carcinoma. Cancer Immunol Immunother 2024; 73:166. [PMID: 38954042 PMCID: PMC11219697 DOI: 10.1007/s00262-024-03755-w] [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: 12/03/2023] [Accepted: 06/03/2024] [Indexed: 07/04/2024]
Abstract
BACKGROUND Vulvar squamous cell carcinoma (VSCC) arises after an HPV infection or the mutation of p53 or other driver genes and is treated by mutilating surgery and/or (chemo) radiation, with limited success and high morbidity. In-depth information on the immunological make up of VSCC is pivotal to assess whether immunotherapy may form an alternative treatment. METHODS A total of 104 patient samples, comprising healthy vulva (n = 27) and VSCC (n = 77), were analyzed. Multispectral immunofluorescence (15 markers) was used to study both the myeloid and lymphoid immune cell composition, and this was linked to differences in transcriptomics (NanoString nCounter, 1258 genes) and in survival (Kaplan-Meier analyses). RESULTS Healthy vulva and VSCC are both well infiltrated but with different subpopulations of lymphoid and myeloid cells. In contrast to the lymphoid cell infiltrate, the density and composition of the myeloid cell infiltrate strongly differed per VSCC molecular subtype. A relative strong infiltration with epithelial monocytes (HLADR-CD11c-CD14+CD68-CD163-CD33-) was prognostic for improved survival, independent of T cell infiltration, disease stage or molecular subtype. A strong infiltration with T cells and/or monocytes was associated with drastic superior survival: 5-year survival > 90% when either one is high, versus 40% when both are low (p < 0.001). CONCLUSION A hot myeloid and/or lymphoid infiltrate predicts excellent survival in VSCC. Based on the response of similarly high-infiltrated other tumor types, we have started to explore the potential of neoadjuvant checkpoint blockade in VSCC.
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Affiliation(s)
- Ziena Abdulrahman
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
| | - Kim E Kortekaas
- Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marij J P Welters
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
| | | | - Sjoerd H van der Burg
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
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14
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Efe G, Rustgi AK, Prives C. p53 at the crossroads of tumor immunity. NATURE CANCER 2024; 5:983-995. [PMID: 39009816 DOI: 10.1038/s43018-024-00796-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 06/03/2024] [Indexed: 07/17/2024]
Abstract
The p53 tumor suppressor protein has a plethora of cell-intrinsic functions and consequences that impact diverse cell types and tissues. Recent studies are beginning to unravel how wild-type and mutant p53 work in distinct ways to modulate tumor immunity. This sets up a disequilibrium between tumor immunosurveillance and escape therefrom. The ability to exploit this emerging knowledge for translational approaches may shape immunotherapy and targeted therapeutics in the future, especially in combinatorial settings.
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Affiliation(s)
- Gizem Efe
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Anil K Rustgi
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
- Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
| | - Carol Prives
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
- Department of Biological Sciences, Columbia University, New York, NY, USA.
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15
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Lavi Arab F, Hoseinzadeh A, Hafezi F, Sadat Mohammadi F, Zeynali F, Hadad Tehran M, Rostami A. Mesenchymal stem cell-derived exosomes for management of prostate cancer: An updated view. Int Immunopharmacol 2024; 134:112171. [PMID: 38701539 DOI: 10.1016/j.intimp.2024.112171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 04/16/2024] [Accepted: 04/27/2024] [Indexed: 05/05/2024]
Abstract
Prostate cancer represents the second most prevalent form of cancer found in males, and stands as the fifth primary contributor to cancer-induced mortality on a global scale. Research has shown that transplanted mesenchymal stem cells (MSCs) can migrate by homing to tumor sites in the body. In prostate cancer, researchers have explored the fact that MSC-based therapies (including genetically modified delivery vehicles or vectors) and MSC-derived exosomes are emerging as attractive options to improve the efficacy and safety of traditional cancer therapies. In addition, researchers have reported new insights into the application of extracellular vesicle (EV)-MSC therapy as a novel treatment option that could provide a more effective and targeted approach to prostate cancer treatment. Moreover, the new generation of exosomes, which contain biologically functional molecules as signal transducers between cells, can simultaneously deliver different therapeutic agents and induce an anti-tumor phenotype in immune cells and their recruitment to the tumor site. The results of the current research on the use of MSCs in the treatment of prostate cancer may be helpful to researchers and clinicians working in this field. Nevertheless, it is crucial to emphasize that although dual-role MSCs show promise as a therapeutic modality for managing prostate cancer, further investigation is imperative to comprehensively grasp their safety and effectiveness. Ongoing clinical trials are being conducted to assess the viability of MSCs in the management of prostate cancer. The results of these trials will help determine the viability of this approach. Based on the current literature, engineered MSCs-EV offer great potential for application in targeted tumor therapy.
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Affiliation(s)
- Fahimeh Lavi Arab
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Akram Hoseinzadeh
- Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.; Cancer Research Center, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Hafezi
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Sadat Mohammadi
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farid Zeynali
- Department of Urology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Melika Hadad Tehran
- Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Amirreza Rostami
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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16
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Liu Y, Su Z, Tavana O, Gu W. Understanding the complexity of p53 in a new era of tumor suppression. Cancer Cell 2024; 42:946-967. [PMID: 38729160 PMCID: PMC11190820 DOI: 10.1016/j.ccell.2024.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/15/2024] [Accepted: 04/16/2024] [Indexed: 05/12/2024]
Abstract
p53 was discovered 45 years ago as an SV40 large T antigen binding protein, coded by the most frequently mutated TP53 gene in human cancers. As a transcription factor, p53 is tightly regulated by a rich network of post-translational modifications to execute its diverse functions in tumor suppression. Although early studies established p53-mediated cell-cycle arrest, apoptosis, and senescence as the classic barriers in cancer development, a growing number of new functions of p53 have been discovered and the scope of p53-mediated anti-tumor activity is largely expanded. Here, we review the complexity of different layers of p53 regulation, and the recent advance of the p53 pathway in metabolism, ferroptosis, immunity, and others that contribute to tumor suppression. We also discuss the challenge regarding how to activate p53 function specifically effective in inhibiting tumor growth without harming normal homeostasis for cancer therapy.
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Affiliation(s)
- Yanqing Liu
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Zhenyi Su
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Omid Tavana
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Wei Gu
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
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17
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Chen X, Gong L, Wang Y, Ye C, Guo H, Gao S, Chen J, Wang Z, Gao Y. IL-23 inhibitor enhances the effects of PTEN DNA-loaded lipid nanoparticles for metastatic CRPC therapy. Front Pharmacol 2024; 15:1388613. [PMID: 38898927 PMCID: PMC11186457 DOI: 10.3389/fphar.2024.1388613] [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: 02/20/2024] [Accepted: 05/09/2024] [Indexed: 06/21/2024] Open
Abstract
Introduction: Metastatic castration-resistant prostate cancer (mCRPC) patients face challenges due to limited treatment options. About 50% of patients with mCRPC have a functional loss of phosphatase and tensin homology deleted on chromosome 10 (PTEN), leading to tumor progression, metastasis, and immune suppression. Moreover, elevated IL-23 produced by myeloid-derived suppressor cells (MDSCs) is found in CRPC patients, driving tumor progression. Therefore, a combination strategy based on PTEN restoration and IL-23 inhibition may block CRPC progression and metastasis. Methods: The antitumor effect of restoring PTEN expression combined with the IL-23 inhibitor Apilimod was studied in a mouse model of bone metastasis CRPC and mouse prostate cancer RM-1 cells. To verify the targeting ability of PTEN DNA coated with lipid nanoparticles (LNP@PTEN) in vitro and in vivo. In addition, RT-qPCR and flow cytometry were used to investigate the related mechanisms of the antitumor effect of LNP@PTEN combined with Apilimod. Results: LNPs exhibited significant tumor-targeting and tumor accumulation capabilities both in vitro and in vivo, enhancing PTEN expression and therapeutic efficacy. Additionally, the combination of LNP@PTEN with the IL-23 inhibitor Apilimod demonstrated enhanced inhibition of tumor growth, invasion, and metastasis (particularly secondary organ metastasis) compared to other groups, and extended the survival of mice to 41 days, providing a degree of bone protection. These effects may be attributed to the PTEN function restoration combined with IL-23 inhibition, which help reverse immune suppression in the tumor microenvironment by reducing MDSCs recruitment and increasing the CD8+/CD4+ T cell ratio. Discussion: In summary, these findings highlight the potential of LNPs for delivering gene therapeutic agents. And the combination of LNP@PTEN with Apilimod could achieve anti-tumor effects and improve tumor microenvironment. This combinational strategy opens new avenues for the treatment of mCRPC.
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Affiliation(s)
- Xinlu Chen
- School of Pharmacy, Fudan University, Shanghai, China
- Department of Pharmacy, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Luyao Gong
- School of Pharmacy, Fudan University, Shanghai, China
| | - Yuanyuan Wang
- School of Pharmacy, Fudan University, Shanghai, China
| | - Chen Ye
- Department of Pharmacy, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Huanhuan Guo
- Department of Pharmacy, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Shen Gao
- Department of Pharmacy, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jiyuan Chen
- Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhuo Wang
- School of Pharmacy, Fudan University, Shanghai, China
| | - Yuan Gao
- School of Pharmacy, Fudan University, Shanghai, China
- Department of Pharmacy, Changhai Hospital, Naval Medical University, Shanghai, China
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18
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Kim Y, Choi J, Kim EH, Park W, Jang H, Jang Y, Chi S, Kweon D, Lee K, Kim SH, Yang Y. Design of PD-L1-Targeted Lipid Nanoparticles to Turn on PTEN for Efficient Cancer Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2309917. [PMID: 38520717 PMCID: PMC11165541 DOI: 10.1002/advs.202309917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 03/15/2024] [Indexed: 03/25/2024]
Abstract
Lipid nanoparticles (LNPs) exhibit remarkable mRNA delivery efficiency, yet their majority accumulate in the liver or spleen after injection. Tissue-specific mRNA delivery can be achieved through modulating LNP properties, such as tuning PEGylation or varying lipid components systematically. In this paper, a streamlined method is used for incorporating tumor-targeting peptides into the LNPs; the programmed death ligand 1 (PD-L1) binding peptides are conjugated to PEGylated lipids via a copper-free click reaction, and directly incorporated into the LNP composition (Pep LNPs). Notably, Pep LNPs display robust interaction with PD-L1 proteins, which leads to the uptake of LNPs into PD-L1 overexpressing cancer cells both in vitro and in vivo. To evaluate anticancer immunotherapy mediated by restoring tumor suppressor, mRNA encoding phosphatase and tensin homolog (PTEN) is delivered via Pep LNPs to PTEN-deficient triple-negative breast cancers (TNBCs). Pep LNPs loaded with PTEN mRNA specifically promotes autophagy-mediated immunogenic cell death in 4T1 tumors, resulting in effective anticancer immune responses. This study highlights the potential of tumor-targeted LNPs for mRNA-based cancer therapy.
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Affiliation(s)
- Yelee Kim
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- Department of Life SciencesKorea UniversitySeoul02841Republic of Korea
| | - Jiwoong Choi
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
| | - Eun Hye Kim
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- Department of Life SciencesKorea UniversitySeoul02841Republic of Korea
| | - Wonbeom Park
- Department of Integrative BiotechnologySungkyunkwan UniversitySuwon16419Republic of Korea
| | - Hochung Jang
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- Division of Bio‐Medical Science and TechnologyKIST SchoolKorea University of Science and TechnologySeoul02792Republic of Korea
| | - Yeongji Jang
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- Department of Life SciencesKorea UniversitySeoul02841Republic of Korea
| | - Sung‐Gil Chi
- Department of Life SciencesKorea UniversitySeoul02841Republic of Korea
| | - Dae‐Hyuk Kweon
- Department of Integrative BiotechnologySungkyunkwan UniversitySuwon16419Republic of Korea
| | - Kyuri Lee
- College of Pharmacy and Research Institute of Pharmaceutical SciencesGyeongsang National UniversityJinju52828Republic of Korea
| | - Sun Hwa Kim
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- KU‐KIST Graduate School of Converging Science and TechnologyKorea UniversitySeoul02841Republic of Korea
| | - Yoosoo Yang
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- Division of Bio‐Medical Science and TechnologyKIST SchoolKorea University of Science and TechnologySeoul02792Republic of Korea
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19
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Sun C, Wang S, Ma Z, Zhou J, Ding Z, Yuan G, Pan Y. Neutrophils in glioma microenvironment: from immune function to immunotherapy. Front Immunol 2024; 15:1393173. [PMID: 38779679 PMCID: PMC11109384 DOI: 10.3389/fimmu.2024.1393173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/25/2024] [Indexed: 05/25/2024] Open
Abstract
Glioma is a malignant tumor of the central nervous system (CNS). Currently, effective treatment options for gliomas are still lacking. Neutrophils, as an important member of the tumor microenvironment (TME), are widely distributed in circulation. Recently, the discovery of cranial-meningeal channels and intracranial lymphatic vessels has provided new insights into the origins of neutrophils in the CNS. Neutrophils in the brain may originate more from the skull and adjacent vertebral bone marrow. They cross the blood-brain barrier (BBB) under the action of chemokines and enter the brain parenchyma, subsequently migrating to the glioma TME and undergoing phenotypic changes upon contact with tumor cells. Under glycolytic metabolism model, neutrophils show complex and dual functions in different stages of cancer progression, including participation in the malignant progression, immune suppression, and anti-tumor effects of gliomas. Additionally, neutrophils in the TME interact with other immune cells, playing a crucial role in cancer immunotherapy. Targeting neutrophils may be a novel generation of immunotherapy and improve the efficacy of cancer treatments. This article reviews the molecular mechanisms of neutrophils infiltrating the central nervous system from the external environment, detailing the origin, functions, classifications, and targeted therapies of neutrophils in the context of glioma.
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Affiliation(s)
- Chao Sun
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Siwen Wang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Zhen Ma
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Jinghuan Zhou
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Zilin Ding
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Guoqiang Yuan
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Yawen Pan
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
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20
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Lopez-Bujanda ZA, Hadavi SH, Ruiz De Porras V, Martínez-Balibrea E, Dallos MC. Chemotactic signaling pathways in prostate cancer: Implications in the tumor microenvironment and as potential therapeutic targets. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 388:162-205. [PMID: 39260936 DOI: 10.1016/bs.ircmb.2024.03.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Prostate cancer (PCa) stands as a significant global health concern, ranking among the leading causes of cancer deaths in men. While there are several treatment modalities for localized PCa, metastatic castration-resistant PCa (mCRPC) remains incurable. Despite therapeutic advancements showing promise in mCRPC, their impact on overall survival has been limited. This chapter explores the process by which tumors form, reviews our current understanding of PCa progression to mCRPC, and addresses the challenges of boosting anti-tumor immune responses in these tumors. It specifically discusses how chemotactic signaling affects the tumor microenvironment and its role in immune evasion and cancer progression. The chapter further examines the rationale of directly or indirectly targeting these pathways as adjuvant therapies for mCRPC, highlighting recent pre-clinical and clinical studies currently underway. The discussion emphasizes the potential of targeting specific chemokines and chemokine receptors as combination therapies with mainstream treatments for PCa and mCRPC to maximize long-term survival for this deadly disease.
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Affiliation(s)
- Zoila A Lopez-Bujanda
- Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, United States.
| | - Shawn H Hadavi
- Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States
| | - Vicenç Ruiz De Porras
- Badalona Applied Research Group of Oncology (B-ARGO), Catalan Institute of Oncology, Badalona, BCN, Spain; CARE program, Germans Trias i Pujol Research Institute (IGTP), Badalona, BCN, Spain
| | - Eva Martínez-Balibrea
- CARE program, Germans Trias i Pujol Research Institute (IGTP), Badalona, BCN, Spain; ProCURE Program, Catalan Institute of Oncology, Badalona, BCN, Spain
| | - Matthew C Dallos
- Memorial Solid Tumor Group, Memorial Sloan Kettering Cancer Center, New York, NY, United States
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21
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Chauhan S, Jaiswal S, Jakhmola V, Singh B, Bhattacharya S, Garg M, Sengupta S. Potential role of p53 deregulation in modulating immune responses in human malignancies: A paradigm to develop immunotherapy. Cancer Lett 2024; 588:216766. [PMID: 38408603 PMCID: PMC7615729 DOI: 10.1016/j.canlet.2024.216766] [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: 01/19/2024] [Revised: 02/22/2024] [Accepted: 02/22/2024] [Indexed: 02/28/2024]
Abstract
The crucial role played by the oncogenic expression of TP53, stemming from mutation or amyloid formation, in various human malignancies has been extensively studied over the past two decades. Interestingly, the potential role of TP53 as a crucial player in modulating immune responses has provided new insight into the field of cancer biology. The loss of p53's transcriptional functions and/or the acquisition of tumorigenic properties can efficiently modulate the recruitment and functions of myeloid and lymphoid cells, ultimately leading to the evasion of immune responses in human tumors. Consequently, the oncogenic nature of the tumor suppressor p53 can dynamically alter the function of immune cells, providing support for tumor progression and metastasis. This review comprehensively explores the dual role of p53 as both the guardian of the genome and an oncogenic driver, especially in the context of regulation of autophagy, apoptosis, the tumor microenvironment, immune cells, innate immunity, and adaptive immune responses. Additionally, the focus of this review centers on how p53 status in the immune response can be harnessed for the development of tailored therapeutic strategies and their potential application in immunotherapy against human malignancies.
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Affiliation(s)
- Shivi Chauhan
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noda, 201313, India
| | - Shivani Jaiswal
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noda, 201313, India
| | - Vibhuti Jakhmola
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noda, 201313, India
| | - Bhavana Singh
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noda, 201313, India
| | - Sujata Bhattacharya
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noda, 201313, India
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noda, 201313, India.
| | - Shinjinee Sengupta
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noda, 201313, India.
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22
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Li Z, Mo F, Guo K, Ren S, Wang Y, Chen Y, Schwartz PB, Richmond N, Liu F, Ronnekleiv-Kelly SM, Hu Q. Nanodrug-bacteria conjugates-mediated oncogenic collagen depletion enhances immune checkpoint blockade therapy against pancreatic cancer. MED 2024; 5:348-367.e7. [PMID: 38521069 DOI: 10.1016/j.medj.2024.02.012] [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: 06/25/2023] [Revised: 11/15/2023] [Accepted: 02/27/2024] [Indexed: 03/25/2024]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) cancer cells specifically produce abnormal oncogenic collagen to bind with integrin α3β1 receptor and activate the downstream focal adhesion kinase (FAK), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, this promotes immunosuppression and tumor proliferation and restricts the response rate of clinical cancer immunotherapies. METHODS Here, by leveraging the hypoxia tropism and excellent motility of the probiotic Escherichia coli strain Nissle 1917 (ECN), we developed nanodrug-bacteria conjugates to penetrate the extracellular matrix (ECM) and shuttle the surface-conjugated protein cages composed of collagenases and anti-programmed death-ligand 1 (PD-L1) antibodies to PDAC tumor parenchyma. FINDINGS We found the oncogenic collagen expression in human pancreatic cancer patients and demonstrated its interaction with integrin α3β1. We proved that reactive oxygen species (ROS) in the microenvironment of PDAC triggered collagenase release to degrade oncogenic collagen and block integrin α3β1-FAK signaling pathway, thus overcoming the immunosuppression and synergizing with anti-PD-L1 immunotherapy. CONCLUSIONS Collectively, our study highlights the significance of oncogenic collagen in PDAC immunotherapy, and consequently, we developed a therapeutic strategy that can deplete oncogenic collagen to synergize with immune checkpoint blockade for enhanced PDAC treatment efficacy. FUNDING This work was supported by the University of Wisconsin Carbone Cancer Center Research Collaborative and Pancreas Cancer Research Task Force, UWCCC Transdisciplinary Cancer Immunology-Immunotherapy Pilot Project, and the start-up package from the University of Wisconsin-Madison (to Q.H.).
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Affiliation(s)
- Zhaoting Li
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Fanyi Mo
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Kai Guo
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Shuai Ren
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Yixin Wang
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Yu Chen
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Patrick B Schwartz
- Department of Surgery, Division of Surgical Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Nathaniel Richmond
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Fengyuan Liu
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Sean M Ronnekleiv-Kelly
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Surgery, Division of Surgical Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Quanyin Hu
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA.
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23
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De Velasco MA, Kura Y, Fujita K, Uemura H. Moving toward improved immune checkpoint immunotherapy for advanced prostate cancer. Int J Urol 2024; 31:307-324. [PMID: 38167824 DOI: 10.1111/iju.15378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 12/10/2023] [Indexed: 01/05/2024]
Abstract
Human prostate cancer is a heterogenous malignancy that responds poorly to immunotherapy targeting immune checkpoints. The immunosuppressive tumor microenvironment that is typical of human prostate cancer has been the main obstacle to these treatments. The effectiveness of these therapies is also hindered by acquired resistance, leading to slow progress in prostate cancer immunotherapy. Results from the highly anticipated late-stage clinical trials of PD-1/PD-L1 immune checkpoint blockade in patients with advanced prostate cancer have highlighted some of the obstacles to immunotherapy. Despite the setbacks, there is much that has been learned about the mechanisms that drive resistance, and new strategies are being developed and tested. Here, we review the status of immune checkpoint blockade and the immunosuppressive tumor microenvironment and discuss factors contributing to innate and adaptive resistance to immune checkpoint blockade within the context of prostate cancer. We then examine current strategies aiming to overcome these challenges as well as prospects.
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Affiliation(s)
- Marco A De Velasco
- Department of Genome Biology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Yurie Kura
- Department of Genome Biology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Kazutoshi Fujita
- Department of Urology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Hirotsugu Uemura
- Department of Urology, Kindai University Faculty of Medicine, Osakasayama, Japan
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24
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Watanabe F, Hollingsworth EW, Bartley JM, Wisehart L, Desai R, Hartlaub AM, Hester ME, Schiapparelli P, Quiñones-Hinojosa A, Imitola J. Patient-derived organoids recapitulate glioma-intrinsic immune program and progenitor populations of glioblastoma. PNAS NEXUS 2024; 3:pgae051. [PMID: 38384384 PMCID: PMC10879747 DOI: 10.1093/pnasnexus/pgae051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 01/17/2024] [Indexed: 02/23/2024]
Abstract
Glioblastoma multiforme (GBM) is a highly lethal human cancer thought to originate from a self-renewing and therapeutically-resistant population of glioblastoma stem cells (GSCs). The intrinsic mechanisms enacted by GSCs during 3D tumor formation, however, remain unclear, especially in the stages prior to angiogenic/immunological infiltration. In this study, we performed a deep characterization of the genetic, immune, and metabolic profiles of GBM organoids from several patient-derived GSCs (GBMO). Despite being devoid of immune cells, transcriptomic analysis across GBMO revealed a surprising immune-like molecular program, enriched in cytokine, antigen presentation and processing, T-cell receptor inhibitors, and interferon genes. We find two important cell populations thought to drive GBM progression, Special AT-rich sequence-binding protein 2 (SATB2+) and homeodomain-only protein homeobox (HOPX+) progenitors, contribute to this immune landscape in GBMO and GBM in vivo. These progenitors, but not other cell types in GBMO, are resistant to conventional GBM therapies, temozolomide and irradiation. Our work defines a novel intrinsic immune-like landscape in GBMO driven, in part, by SATB2+ and HOPX+ progenitors and deepens our understanding of the intrinsic mechanisms utilized by GSCs in early GBM formation.
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Affiliation(s)
- Fumihiro Watanabe
- Laboratory of Neural Stem Cells and Functional Neurogenetics, Department of Neurology, UConn Health Brain and Spine Institute, 5 Munson Road, Farmington, CT 06030, USA
- Departments of Neuroscience, Neurology, Genetics and Genome Sciences, UConn Health, Farmington, CT 06030, USA
| | - Ethan W Hollingsworth
- Laboratory of Neural Stem Cells and Functional Neurogenetics, Department of Neurology, UConn Health Brain and Spine Institute, 5 Munson Road, Farmington, CT 06030, USA
- Departments of Neuroscience, Neurology, Genetics and Genome Sciences, UConn Health, Farmington, CT 06030, USA
| | | | - Lauren Wisehart
- Laboratory of Neural Stem Cells and Functional Neurogenetics, Department of Neurology, UConn Health Brain and Spine Institute, 5 Munson Road, Farmington, CT 06030, USA
| | - Rahil Desai
- Laboratory of Neural Stem Cells and Functional Neurogenetics, Department of Neurology, UConn Health Brain and Spine Institute, 5 Munson Road, Farmington, CT 06030, USA
| | - Annalisa M Hartlaub
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43215, USA
| | - Mark E Hester
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43215, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Paula Schiapparelli
- Department of Neurosurgery, Brain Tumor Stem Cell Laboratory, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Alfredo Quiñones-Hinojosa
- Department of Neurosurgery, Brain Tumor Stem Cell Laboratory, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Jaime Imitola
- Laboratory of Neural Stem Cells and Functional Neurogenetics, Department of Neurology, UConn Health Brain and Spine Institute, 5 Munson Road, Farmington, CT 06030, USA
- Departments of Neuroscience, Neurology, Genetics and Genome Sciences, UConn Health, Farmington, CT 06030, USA
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25
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Zou Y, Yuan Y, Zhou Q, Yue Z, Liu J, Fan L, Xu H, Xin L. The Role of Methionine Restriction in Gastric Cancer: A Summary of Mechanisms and a Discussion on Tumor Heterogeneity. Biomolecules 2024; 14:161. [PMID: 38397398 PMCID: PMC10887009 DOI: 10.3390/biom14020161] [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: 12/09/2023] [Revised: 01/18/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Gastric cancer is ranked as the fifth most prevalent cancer globally and has long been a topic of passionate discussion among numerous individuals. However, the incidence of gastric cancer in society has not decreased, but instead has shown a gradual increase in recent years. For more than a decade, the treatment effect of gastric cancer has not been significantly improved. This is attributed to the heterogeneity of cancer, which makes popular targeted therapies ineffective. Methionine is an essential amino acid, and many studies have shown that it is involved in the development of gastric cancer. Our study aimed to review the literature on methionine and gastric cancer, describing its mechanism of action to show that tumor heterogeneity in gastric cancer does not hinder the effectiveness of methionine-restricted therapies. This research also aimed to provide insight into the inhibition of gastric cancer through metabolic reprogramming with methionine-restricted therapies, thereby demonstrating their potential as adjuvant treatments for gastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | - Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang 330006, China; (Y.Z.); (Y.Y.); (Q.Z.); (Z.Y.); (J.L.); (L.F.); (H.X.)
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26
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Ghorani E, Swanton C, Quezada SA. Cancer cell-intrinsic mechanisms driving acquired immune tolerance. Immunity 2023; 56:2270-2295. [PMID: 37820584 DOI: 10.1016/j.immuni.2023.09.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 09/11/2023] [Accepted: 09/11/2023] [Indexed: 10/13/2023]
Abstract
Immune evasion is a hallmark of cancer, enabling tumors to survive contact with the host immune system and evade the cycle of immune recognition and destruction. Here, we review the current understanding of the cancer cell-intrinsic factors driving immune evasion. We focus on T cells as key effectors of anti-cancer immunity and argue that cancer cells evade immune destruction by gaining control over pathways that usually serve to maintain physiological tolerance to self. Using this framework, we place recent mechanistic advances in the understanding of cancer immune evasion into broad categories of control over T cell localization, antigen recognition, and acquisition of optimal effector function. We discuss the redundancy in the pathways involved and identify knowledge gaps that must be overcome to better target immune evasion, including the need for better, routinely available tools that incorporate the growing understanding of evasion mechanisms to stratify patients for therapy and trials.
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Affiliation(s)
- Ehsan Ghorani
- Cancer Immunology and Immunotherapy Unit, Department of Surgery and Cancer, Imperial College London, London, UK; Department of Medical Oncology, Imperial College London Hospitals, London, UK.
| | - Charles Swanton
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK
| | - Sergio A Quezada
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, UK.
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27
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Liu S, Wu W, Du Y, Yin H, Chen Q, Yu W, Wang W, Yu J, Liu L, Lou W, Pu N. The evolution and heterogeneity of neutrophils in cancers: origins, subsets, functions, orchestrations and clinical applications. Mol Cancer 2023; 22:148. [PMID: 37679744 PMCID: PMC10483725 DOI: 10.1186/s12943-023-01843-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 08/14/2023] [Indexed: 09/09/2023] Open
Abstract
Neutrophils, the most prevalent innate immune cells in humans, have garnered significant attention in recent years due to their involvement in cancer progression. This comprehensive review aimed to elucidate the important roles and underlying mechanisms of neutrophils in cancer from the perspective of their whole life cycle, tracking them from development in the bone marrow to circulation and finally to the tumor microenvironment (TME). Based on an understanding of their heterogeneity, we described the relationship between abnormal neutrophils and clinical manifestations in cancer. Specifically, we explored the function, origin, and polarization of neutrophils within the TME. Furthermore, we also undertook an extensive analysis of the intricate relationship between neutrophils and clinical management, including neutrophil-based clinical treatment strategies. In conclusion, we firmly assert that directing future research endeavors towards comprehending the remarkable heterogeneity exhibited by neutrophils is of paramount importance.
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Affiliation(s)
- Siyao Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wenchuan Wu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yueshan Du
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Hanlin Yin
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Qiangda Chen
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Weisheng Yu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wenquan Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jun Yu
- Departments of Medicine and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Liang Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China.
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Wenhui Lou
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China.
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Ning Pu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China.
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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28
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Carlsen L, Zhang S, Tian X, De La Cruz A, George A, Arnoff TE, El-Deiry WS. The role of p53 in anti-tumor immunity and response to immunotherapy. Front Mol Biosci 2023; 10:1148389. [PMID: 37602328 PMCID: PMC10434531 DOI: 10.3389/fmolb.2023.1148389] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 07/04/2023] [Indexed: 08/22/2023] Open
Abstract
p53 is a transcription factor that regulates the expression of genes involved in tumor suppression. p53 mutations mediate tumorigenesis and occur in approximately 50% of human cancers. p53 regulates hundreds of target genes that induce various cell fates including apoptosis, cell cycle arrest, and DNA damage repair. p53 also plays an important role in anti-tumor immunity by regulating TRAIL, DR5, TLRs, Fas, PKR, ULBP1/2, and CCL2; T-cell inhibitory ligand PD-L1; pro-inflammatory cytokines; immune cell activation state; and antigen presentation. Genetic alteration of p53 can contribute to immune evasion by influencing immune cell recruitment to the tumor, cytokine secretion in the TME, and inflammatory signaling pathways. In some contexts, p53 mutations increase neoantigen load which improves response to immune checkpoint inhibition. Therapeutic restoration of mutated p53 can restore anti-cancer immune cell infiltration and ameliorate pro-tumor signaling to induce tumor regression. Indeed, there is clinical evidence to suggest that restoring p53 can induce an anti-cancer immune response in immunologically cold tumors. Clinical trials investigating the combination of p53-restoring compounds or p53-based vaccines with immunotherapy have demonstrated anti-tumor immune activation and tumor regression with heterogeneity across cancer type. In this Review, we discuss the impact of wild-type and mutant p53 on the anti-tumor immune response, outline clinical progress as far as activating p53 to induce an immune response across a variety of cancer types, and highlight open questions limiting effective clinical translation.
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Affiliation(s)
- Lindsey Carlsen
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
- Pathobiology Graduate Program, Warren Alpert Medical School, Brown University, Providence, RI, United States
| | - Shengliang Zhang
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
| | - Xiaobing Tian
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
| | - Arielle De La Cruz
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
| | - Andrew George
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
| | - Taylor E. Arnoff
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
| | - Wafik S. El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
- Pathobiology Graduate Program, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Hematology-Oncology Division, Department of Medicine, Lifespan Health System and Warren Alpert Medical School, Brown University, Providence, RI, United States
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Yeo AT, Shah R, Aliazis K, Pal R, Xu T, Zhang P, Rawal S, Rose CM, Varn FS, Appleman VA, Yoon J, Varma H, Gygi SP, Verhaak RG, Boussiotis VA, Charest A. Driver Mutations Dictate the Immunologic Landscape and Response to Checkpoint Immunotherapy of Glioblastoma. Cancer Immunol Res 2023; 11:629-645. [PMID: 36881002 PMCID: PMC10155040 DOI: 10.1158/2326-6066.cir-22-0655] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 12/20/2022] [Accepted: 03/03/2023] [Indexed: 03/08/2023]
Abstract
The composition of the tumor immune microenvironment (TIME) is considered a key determinant of patients' response to immunotherapy. The mechanisms underlying TIME formation and development over time are poorly understood. Glioblastoma (GBM) is a lethal primary brain cancer for which there are no curative treatments. GBMs are immunologically heterogeneous and impervious to checkpoint blockade immunotherapies. Utilizing clinically relevant genetic mouse models of GBM, we identified distinct immune landscapes associated with expression of EGFR wild-type and mutant EGFRvIII cancer driver mutations. Over time, accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) was more pronounced in EGFRvIII-driven GBMs and was correlated with resistance to PD-1 and CTLA-4 combination checkpoint blockade immunotherapy. We determined that GBM-secreted CXCL1/2/3 and PMN-MDSC-expressed CXCR2 formed an axis regulating output of PMN-MDSCs from the bone marrow leading to systemic increase in these cells in the spleen and GBM tumor-draining lymph nodes. Pharmacologic targeting of this axis induced a systemic decrease in the numbers of PMN-MDSC, facilitated responses to PD-1 and CTLA-4 combination checkpoint blocking immunotherapy, and prolonged survival in mice bearing EGFRvIII-driven GBM. Our results uncover a relationship between cancer driver mutations, TIME composition, and sensitivity to checkpoint blockade in GBM and support the stratification of patients with GBM for checkpoint blockade therapy based on integrated genotypic and immunologic profiles.
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Affiliation(s)
- Alan T. Yeo
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- Sackler School of Graduate Studies, Tufts University School of Medicine, Boston, Massachusetts
| | - Rushil Shah
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Konstantinos Aliazis
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Rinku Pal
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Tuoye Xu
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Piyan Zhang
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Shruti Rawal
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | | | - Frederick S. Varn
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut
| | - Vicky A. Appleman
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Joon Yoon
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Hemant Varma
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Steven P. Gygi
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
| | - Roel G.W. Verhaak
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut
| | - Vassiliki A. Boussiotis
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Al Charest
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
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30
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Wang D, Cheng C, Chen X, Wang J, Liu K, Jing N, Xu P, Xi X, Sun Y, Ji Z, Zhao H, He Y, Zhang K, Du X, Dong B, Fang Y, Zhang P, Qian X, Xue W, Gao WQ, Zhu HH. IL-1β Is an Androgen-Responsive Target in Macrophages for Immunotherapy of Prostate Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023:e2206889. [PMID: 37092583 DOI: 10.1002/advs.202206889] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/03/2023] [Indexed: 05/03/2023]
Abstract
Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa-infiltrated immune cells and the impact of androgen deprivation therapy (ADT), the first-line treatment for advanced PCa, on the PCa immune microenvironment remains limited. On the other hand, immune checkpoint blockade has revolutionized the treatment of certain cancer types, but fails to achieve any benefit in advanced PCa, due to an immune suppressive environment. In this study, it is reported that AR signaling pathway is evidently activated in tumor-associated macrophages (TAMs) of PCa both in mice and humans. AR acts as a transcriptional repressor for IL1B in TAMs. ADT releases the restraint of AR on IL1B and therefore leads to an excessive expression and secretion of IL-1β in TAMs. IL-1β induces myeloid-derived suppressor cells (MDSCs) accumulation that inhibits the activation of cytotoxic T cells, leading to the immune suppressive microenvironment. Critically, anti-IL-1β antibody coupled with ADT and the immune checkpoint inhibitor anti-PD-1 antibody exerts a stronger anticancer effect on PCa following castration. Together, IL-1β is an important androgen-responsive immunotherapeutic target for advanced PCa.
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Affiliation(s)
- Deng Wang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China
| | - Chaping Cheng
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Xinyu Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Jinming Wang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Kaiyuan Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Na Jing
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China
| | - Penghui Xu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China
| | - Xialian Xi
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Yujiao Sun
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Zhongzhong Ji
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Huifang Zhao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Yuman He
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Kai Zhang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Xinxing Du
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, P. R. China
| | - Baijun Dong
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, P. R. China
| | - Yuxiang Fang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Pengcheng Zhang
- School of Biomedical Engineering, ShanghaiTech University, Shanghai, 201210, P. R. China
| | - Xueming Qian
- Mabspace Biosciences (Suzhou) Co. Limited, Suzhou, 215123, P. R. China
| | - Wei Xue
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, P. R. China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China
| | - Helen He Zhu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
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31
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Gogola S, Rejzer M, Bahmad HF, Abou-Kheir W, Omarzai Y, Poppiti R. Epithelial-to-Mesenchymal Transition-Related Markers in Prostate Cancer: From Bench to Bedside. Cancers (Basel) 2023; 15:cancers15082309. [PMID: 37190236 DOI: 10.3390/cancers15082309] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/07/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
Prostate cancer (PCa) is the second most frequent type of cancer in men worldwide, with 288,300 new cases and 34,700 deaths estimated in the United States in 2023. Treatment options for early-stage disease include external beam radiation therapy, brachytherapy, radical prostatectomy, active surveillance, or a combination of these. In advanced cases, androgen-deprivation therapy (ADT) is considered the first-line therapy; however, PCa in most patients eventually progresses to castration-resistant prostate cancer (CRPC) despite ADT. Nonetheless, the transition from androgen-dependent to androgen-independent tumors is not yet fully understood. The physiological processes of epithelial-to-non-epithelial ("mesenchymal") transition (EMT) and mesenchymal-to-epithelial transition (MET) are essential for normal embryonic development; however, they have also been linked to higher tumor grade, metastatic progression, and treatment resistance. Due to this association, EMT and MET have been identified as important targets for novel cancer therapies, including CRPC. Here, we discuss the transcriptional factors and signaling pathways involved in EMT, in addition to the diagnostic and prognostic biomarkers that have been identified in these processes. We also tackle the various studies that have been conducted from bench to bedside and the current landscape of EMT-targeted therapies.
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Affiliation(s)
- Samantha Gogola
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Michael Rejzer
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Hisham F Bahmad
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon
| | - Yumna Omarzai
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
- Department of Pathology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Robert Poppiti
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
- Department of Pathology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
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32
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Li X, Zheng C, Xue X, Wu J, Li F, Song D, Li X. Integrated analysis of single-cell and bulk RNA sequencing identifies a signature based on macrophage marker genes involved in prostate cancer prognosis and treatment responsiveness. Funct Integr Genomics 2023; 23:115. [PMID: 37010617 DOI: 10.1007/s10142-023-01037-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/22/2023] [Accepted: 03/22/2023] [Indexed: 04/04/2023]
Abstract
In the tumor microenvironment, tumor-associated macrophages (TAMs) interact with cancer cells and contribute to the progression of solid tumors. Nonetheless, the clinical significance of TAM-related biomarkers in prostate cancer (PCa) is largely unexplored. The present study aimed to construct a macrophage-related signature (MRS) for predicting PCa patient prognosis based on macrophage marker genes. Six cohorts comprising 1056 PCa patients with RNA-Seq and follow-up data were enrolled. Based on macrophage marker genes identified by single-cell RNA-sequencing (scRNA-seq) analysis, univariate analysis, least absolute shrinkage and selection operator (Lasso)-Cox regression, and machine learning procedures were performed to derive a consensus MRS. Receiver operating characteristic curve (ROC), concordance index, and decision curve analyses were used to confirm the predictive capacity of the MRS. The predictive performance of the MRS for recurrence-free survival (RFS) was stable and robust, and the MRS outperformed traditional clinical variables. Furthermore, high-MRS-score patients presented abundant macrophage infiltration and high-expression levels of immune checkpoints (CTLA4, HAVCR2, and CD86). The frequency of mutations was relatively high in the high-MRS-score subgroup. However, the low-MRS-score patients had a better response to immune checkpoint blockade (ICB) and leuprolide-based adjuvant chemotherapy. Notably, abnormal ATF3 expression may be associated with docetaxel and cabazitaxel resistance in PCa cells, T stage, and the Gleason score. In this study, a novel MRS was first developed and validated to accurately predict patient survival outcomes, evaluate immune characteristics, infer therapeutic benefits, and provide an auxiliary tool for personalized therapy.
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Affiliation(s)
- Xiugai Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, China
| | - Chang Zheng
- Department of Clinical Epidemiology, First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Xiaoxia Xue
- Science Experiment Center, China Medical University, Shenyang, 110122, China
| | - Junying Wu
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, China
| | - Fei Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, China
| | - Dan Song
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, China
| | - Xuelian Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, China.
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Vidotto T, Melo CM, Lautert-Dutra W, Chaves LP, Reis RB, Squire JA. Pan-cancer genomic analysis shows hemizygous PTEN loss tumors are associated with immune evasion and poor outcome. Sci Rep 2023; 13:5049. [PMID: 36977733 PMCID: PMC10050165 DOI: 10.1038/s41598-023-31759-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
In tumors, somatic mutations of the PTEN suppressor gene are associated with advanced disease, chemotherapy resistance, and poor survival. PTEN loss of function may occur by inactivating mutation, by deletion, either affecting one copy (hemizygous loss) leading to reduced gene expression or loss of both copies (homozygous) with expression absent. Various murine models have shown that minor reductions in PTEN protein levels strongly influence tumorigenesis. Most PTEN biomarker assays dichotomize PTEN (i.e. presence vs. absence) ignoring the role of one copy loss. We performed a PTEN copy number analysis of 9793 TCGA cases from 30 different tumor types. There were 419 (4.28%) homozygous and 2484 (25.37%) hemizygous PTEN losses. Hemizygous deletions led to reduced PTEN gene expression, accompanied by increased levels of instability and aneuploidy across tumor genomes. Outcome analysis of the pan-cancer cohort showed that losing one copy of PTEN reduced survival to comparable levels as complete loss, and was associated with transcriptomic changes controlling immune response and the tumor microenvironment. Immune cell abundances were significantly altered for PTEN loss, with changes in head and neck, cervix, stomach, prostate, brain, and colon more evident in hemizygous loss tumors. These data suggest that reduced expression of PTEN in tumors with hemizygous loss leads to tumor progression and influences anticancer immune response pathways.
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Affiliation(s)
- T Vidotto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - C M Melo
- Department of Genetics, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - W Lautert-Dutra
- Department of Genetics, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - L P Chaves
- Department of Genetics, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - R B Reis
- Division of Urology, Department of Surgery and Anatomy, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - J A Squire
- Department of Genetics, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada.
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Li X, Wei S, Deng L, Tao H, Liu M, Zhao Z, Du X, Li Y, Hou J. Sex-biased molecular differences in lung adenocarcinoma are ethnic and smoking specific. BMC Pulm Med 2023; 23:99. [PMID: 36964522 PMCID: PMC10039609 DOI: 10.1186/s12890-023-02387-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 03/14/2023] [Indexed: 03/26/2023] Open
Abstract
BACKGROUND Sex-related differences in cancer epidemiology, tumor biology, immune system activity, and pharmacogenomics have been suggested to be important considerations for precision cancer control. Here we elucidated systematically sex biases in genetic variants, gene expression profiles, and immunological landscapes of lung adenocarcinoma patients (LUADs) with different ancestry and smoking status. METHODS Somatic mutation and mRNA expression data of Asian and Non-Asian LUADs were obtained from public databases. Sex-biased genetic mutations, gene expression, biological pathways, and immune infiltration were identified in the context of smoking status and race. RESULTS Among nonsmokers, male-biased mutations were prevalent in Asian LUADs, while few sex-biased mutations were detected in Non-Asian LUADs. EGFR was the only mutation whose frequency was significantly higher in females than males in both Asian and Non-Asian nonsmokers. More genes exhibited sex-biased expression in Non-Asian LUADs compared to Asian LUADs. Moreover, genes distinctly expressed in females were mainly related to immune-related pathways, whereas those in males were more involved in activation of DNA repair, E2F_targets, and MYC_targets pathways. We also detected sex-specific immune infiltration in the context of genetic variation. In EGFR-mutant LUADs, males had a significantly increased infiltration of CD8 + T cells, whereas resting CD4 + memory T cells were more abundant in females. Additionally, in KRAS-mutant LUADs, CD8 + and CD4 + T cells were more abundant in females than males. In addition, we detected all female patients with high SCGB3A2 expression were exclusively sensitive to immunotherapy, while this phenomenon was not observed in male patients. CONCLUSIONS Our findings provided evidence that sex-related molecular and cellular components are involved in shaping tumor distinct genetic and immune features, which might have important impact on personalized targeted and immune therapy.
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Affiliation(s)
- Xuetao Li
- Department of Oncology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Shuquan Wei
- Department of Pulmonary and Critical Care Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China
| | - Liaoyuan Deng
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - HongYan Tao
- Department of Pulmonary Diseases, The Second Affiliated Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Mingkai Liu
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Ziwen Zhao
- Department of Pulmonary and Critical Care Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China
| | - Xin Du
- Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
| | - Yujun Li
- Department of Pulmonary and Critical Care Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.
| | - Jun Hou
- Center for Medical Research On Innovation and Translation, Institute of Clinical Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.
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Zhu Y, Zhao Y, Wen J, Liu S, Huang T, Hatial I, Peng X, Janabi HA, Huang G, Mittlesteadt J, Cheng M, Bhardwaj A, Ashfeld BL, Kao KR, Maeda DY, Dai X, Wiest O, Blagg BS, Lu X, Cheng L, Wan J, Lu X. Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer. Sci Immunol 2023; 8:eade4656. [PMID: 36897957 PMCID: PMC10336890 DOI: 10.1126/sciimmunol.ade4656] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 02/16/2023] [Indexed: 03/12/2023]
Abstract
The noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell-intrinsic oncogenic signaling are increasingly appreciated for their role in shaping the immune landscape. Recently, we identified Pygopus 2 (PYGO2) as the driver oncogene for the amplicon at 1q21.3 in prostate cancer. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the activation and infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/Ido1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the antitumor efficacy of immunotherapies using immune checkpoint blockade (ICB), adoptive cell transfer, or agents inhibiting myeloid-derived suppressor cells. In human prostate cancer samples, Pygo2 expression was inversely correlated with the infiltration of CD8+ T cells. Analysis of the ICB clinical data showed association between high PYGO2 level and worse outcome. Together, our results highlight a potential path to improve immunotherapy using Pygo2-targeted therapy for advanced prostate cancer.
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Affiliation(s)
- Yini Zhu
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Yun Zhao
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Jiling Wen
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Sheng Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Tianhe Huang
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Ishita Hatial
- Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Xiaoxia Peng
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Hawraa Al Janabi
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Gang Huang
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Jackson Mittlesteadt
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Michael Cheng
- Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Atul Bhardwaj
- Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Brandon L. Ashfeld
- Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Kenneth R. Kao
- Terry Fox Cancer Research Labs, Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’s Campus, NL A1B 3V6, Canada
| | | | - Xing Dai
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, USA
| | - Olaf Wiest
- Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Brian S.J. Blagg
- Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Xuemin Lu
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Pathology and Laboratory Medicine, Brown University Warren Alpert Medical School, Lifespan Academic Medical Center, and the Legorreta Cancer Center at Brown University, Providence, RI, USA
| | - Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- School of Informatics and Computing, Indiana University - Purdue University at Indianapolis, Indianapolis, IN 46202, USA
| | - Xin Lu
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
- Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA
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de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell 2023; 41:374-403. [PMID: 36917948 DOI: 10.1016/j.ccell.2023.02.016] [Citation(s) in RCA: 1276] [Impact Index Per Article: 638.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/28/2023] [Accepted: 02/14/2023] [Indexed: 03/14/2023]
Abstract
Cancers represent complex ecosystems comprising tumor cells and a multitude of non-cancerous cells, embedded in an altered extracellular matrix. The tumor microenvironment (TME) includes diverse immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various additional tissue-resident cell types. These host cells were once considered bystanders of tumorigenesis but are now known to play critical roles in the pathogenesis of cancer. The cellular composition and functional state of the TME can differ extensively depending on the organ in which the tumor arises, the intrinsic features of cancer cells, the tumor stage, and patient characteristics. Here, we review the importance of the TME in each stage of cancer progression, from tumor initiation, progression, invasion, and intravasation to metastatic dissemination and outgrowth. Understanding the complex interplay between tumor cell-intrinsic, cell-extrinsic, and systemic mediators of disease progression is critical for the rational development of effective anti-cancer treatments.
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Affiliation(s)
- Karin E de Visser
- Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
| | - Johanna A Joyce
- Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, 1011 Lausanne, Switzerland; Agora Cancer Center Lausanne, and Swiss Cancer Center Léman, 1011 Lausanne, Switzerland.
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Bancaro N, Calì B, Troiani M, Elia AR, Arzola RA, Attanasio G, Lai P, Crespo M, Gurel B, Pereira R, Guo C, Mosole S, Brina D, D'Ambrosio M, Pasquini E, Spataro C, Zagato E, Rinaldi A, Pedotti M, Di Lascio S, Meani F, Montopoli M, Ferrari M, Gallina A, Varani L, Pereira Mestre R, Bolis M, Gillessen Sommer S, de Bono J, Calcinotto A, Alimonti A. Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer. Cancer Cell 2023; 41:602-619.e11. [PMID: 36868226 DOI: 10.1016/j.ccell.2023.02.004] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/20/2022] [Accepted: 02/06/2023] [Indexed: 03/05/2023]
Abstract
Tumor cells promote the recruitment of immunosuppressive neutrophils, a subset of myeloid cells driving immune suppression, tumor proliferation, and treatment resistance. Physiologically, neutrophils are known to have a short half-life. Here, we report the identification of a subset of neutrophils that have upregulated expression of cellular senescence markers and persist in the tumor microenvironment. Senescent-like neutrophils express the triggering receptor expressed on myeloid cells 2 (TREM2) and are more immunosuppressive and tumor-promoting than canonical immunosuppressive neutrophils. Genetic and pharmacological elimination of senescent-like neutrophils decreases tumor progression in different mouse models of prostate cancer. Mechanistically, we have found that apolipoprotein E (APOE) secreted by prostate tumor cells binds TREM2 on neutrophils, promoting their senescence. APOE and TREM2 expression increases in prostate cancers and correlates with poor prognosis. Collectively, these results reveal an alternative mechanism of tumor immune evasion and support the development of immune senolytics targeting senescent-like neutrophils for cancer therapy.
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Affiliation(s)
- Nicolò Bancaro
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Bianca Calì
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Martina Troiani
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Angela Rita Elia
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Rydell Alvarez Arzola
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Giuseppe Attanasio
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Ping Lai
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Mateus Crespo
- The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK
| | - Bora Gurel
- The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK
| | - Rita Pereira
- The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK
| | - Christina Guo
- The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK
| | - Simone Mosole
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Daniela Brina
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Mariantonietta D'Ambrosio
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Emiliano Pasquini
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Clarissa Spataro
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Elena Zagato
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Andrea Rinaldi
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland
| | - Mattia Pedotti
- Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Institute for Research in Biomedicine (IRB), 6500 Bellinzona, Switzerland
| | - Simona Di Lascio
- Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Institute of Oncology of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
| | - Francesco Meani
- Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Institute of Oncology of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
| | - Monica Montopoli
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy; Veneto Institute of Molecular Medicine, Padova, Italy
| | - Matteo Ferrari
- Department of Urology, Ente Ospedaliero Cantonale, Ospedale Regionale di Lugano - Civico USI - Università della Svizzera Italiana, Lugano, Switzerland
| | - Andrea Gallina
- Department of Urology, Ente Ospedaliero Cantonale, Ospedale Regionale di Lugano - Civico USI - Università della Svizzera Italiana, Lugano, Switzerland
| | - Luca Varani
- Institute for Research in Biomedicine (IRB), 6500 Bellinzona, Switzerland
| | - Ricardo Pereira Mestre
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Institute of Oncology of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
| | - Marco Bolis
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Computational Oncology Unit, Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Via Mario Negri 2, 20156 Milano, Italy
| | - Silke Gillessen Sommer
- Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Institute of Oncology of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
| | - Johann de Bono
- The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK
| | - Arianna Calcinotto
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland.
| | - Andrea Alimonti
- Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Institute of Oncology of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland; Veneto Institute of Molecular Medicine, Padova, Italy; Department of Medicine, University of Padova, Padova, Italy; Department of Health Sciences and Technology (D-HEST) ETH Zurich, 8093 Zurich, Switzerland.
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Lei T, Wu G, Xu Y, Zhuang W, Lu J, Han S, Zhuang Y, Dong X, Yang H. Peripheral immune cell profiling of double-hit lymphoma by mass cytometry. BMC Cancer 2023; 23:184. [PMID: 36823603 PMCID: PMC9948356 DOI: 10.1186/s12885-023-10657-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 02/17/2023] [Indexed: 02/25/2023] Open
Abstract
BACKGROUND Double-hit or Triple-hit lymphoma (DHL/THL) is a subset of high-grade B cell lymphoma harboring rearrangements of MYC and BCL2 and/or BCL6, and usually associate with aggressive profile, while current therapies tend to provide poor clinical outcomes and eventually relapsed. Further explorations of DHL at cellular and molecular levels are in demand to offer guidance for clinical activity. METHODS We collected the peripheral blood of DHL patients and diffused large B cell lymphoma (DLBCL) patients from single institute and converted them into PBMC samples. Mass cytometry was then performed to characterize these samples by 42 antibody markers with samples of healthy people as control. We divided the immune cell subtypes based on the expression profile of surface antigens, and the proportion of each cell subtype was also analyzed. By comparing the data of the DLBCL group and the healthy group, we figured out the distinguished immune cell subtypes of DHL patients according to their abundance and marker expression level. We further analyzed the heterogeneity of DHL samples by pairwise comparison based on clinical characteristics. RESULTS We found double-positive T cells (DPT) cells were in a significantly high percentage in DHL patients, whereas the ratio of double-negative T cells (DNT) was largely reduced in patients. Besides, CD38 was uniquely expressed at a high level on some naïve B cells of DHL patients, which could be a marker for the diagnosis of DHL (distinguishing from DLBCL), or even be a drug target for the treatment of DHL. In addition, we illustrated the heterogeneity of DHL patients in terms of immune cell landscape, and highlighted TP53 as a major factor that contributes to the heterogeneity of the T cells profile. CONCLUSION Our study demonstrated the distinct peripheral immune cell profile of DHL patients by contrast to DLBCL patients and healthy people, as well as the heterogeneity within the DHL group, which could provide valuable guidance for the diagnosis and treatment of DHL.
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Affiliation(s)
- Tao Lei
- grid.410726.60000 0004 1797 8419Department of Lymphoma, Institute of Basic Medicine and Cancer (IBMC), The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Chinese Academy of Sciences, Hangzhou, P. R. China
| | - Gongqiang Wu
- grid.268099.c0000 0001 0348 3990Department of Hematology, Dongyang People’s Hospital, Dongyang Hospital Affiliated to Wenzhou Medical University, Dongyang, Zhejiang P. R. China
| | - Yongjin Xu
- grid.410726.60000 0004 1797 8419Department of Lymphoma, Institute of Basic Medicine and Cancer (IBMC), The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Chinese Academy of Sciences, Hangzhou, P. R. China
| | - Weihao Zhuang
- grid.13402.340000 0004 1759 700XHangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
| | - Jialiang Lu
- grid.13402.340000 0004 1759 700XHangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
| | - Shuiyun Han
- grid.410726.60000 0004 1797 8419Department of Lymphoma, Institute of Basic Medicine and Cancer (IBMC), The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Chinese Academy of Sciences, Hangzhou, P. R. China
| | - Yuxin Zhuang
- grid.13402.340000 0004 1759 700XHangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
| | - Xiaowu Dong
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China. .,Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, P. R. China. .,Cancer Center, Zhejiang University, Hangzhou, P. R. China.
| | - Haiyan Yang
- Department of Lymphoma, Institute of Basic Medicine and Cancer (IBMC), The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Chinese Academy of Sciences, Hangzhou, P. R. China.
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van Weverwijk A, de Visser KE. Mechanisms driving the immunoregulatory function of cancer cells. Nat Rev Cancer 2023; 23:193-215. [PMID: 36717668 DOI: 10.1038/s41568-022-00544-4] [Citation(s) in RCA: 131] [Impact Index Per Article: 65.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2022] [Indexed: 01/31/2023]
Abstract
Tumours display an astonishing variation in the spatial distribution, composition and activation state of immune cells, which impacts their progression and response to immunotherapy. Shedding light on the mechanisms that govern the diversity and function of immune cells in the tumour microenvironment will pave the way for the development of more tailored immunomodulatory strategies for the benefit of patients with cancer. Cancer cells, by virtue of their paracrine and juxtacrine communication mechanisms, are key contributors to intertumour heterogeneity in immune contextures. In this Review, we discuss how cancer cell-intrinsic features, including (epi)genetic aberrations, signalling pathway deregulation and altered metabolism, play a key role in orchestrating the composition and functional state of the immune landscape, and influence the therapeutic benefit of immunomodulatory strategies. Moreover, we highlight how targeting cancer cell-intrinsic parameters or their downstream immunoregulatory pathways is a viable strategy to manipulate the tumour immune milieu in favour of antitumour immunity.
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Affiliation(s)
- Antoinette van Weverwijk
- Division of Tumour Biology & Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Karin E de Visser
- Division of Tumour Biology & Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands.
- Department of Immunology, Leiden University Medical Centre, Leiden, Netherlands.
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40
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Álvarez-Prado ÁF, Maas RR, Soukup K, Klemm F, Kornete M, Krebs FS, Zoete V, Berezowska S, Brouland JP, Hottinger AF, Daniel RT, Hegi ME, Joyce JA. Immunogenomic analysis of human brain metastases reveals diverse immune landscapes across genetically distinct tumors. Cell Rep Med 2023; 4:100900. [PMID: 36652909 PMCID: PMC9873981 DOI: 10.1016/j.xcrm.2022.100900] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 09/20/2022] [Accepted: 12/19/2022] [Indexed: 01/19/2023]
Abstract
Brain metastases (BrMs) are the most common form of brain tumors in adults and frequently originate from lung and breast primary cancers. BrMs are associated with high mortality, emphasizing the need for more effective therapies. Genetic profiling of primary tumors is increasingly used as part of the effort to guide targeted therapies against BrMs, and immune-based strategies for the treatment of metastatic cancer are gaining momentum. However, the tumor immune microenvironment (TIME) of BrM is extremely heterogeneous, and whether specific genetic profiles are associated with distinct immune states remains unknown. Here, we perform an extensive characterization of the immunogenomic landscape of human BrMs by combining whole-exome/whole-genome sequencing, RNA sequencing of immune cell populations, flow cytometry, immunofluorescence staining, and tissue imaging analyses. This revealed unique TIME phenotypes in genetically distinct lung- and breast-BrMs, thereby enabling the development of personalized immunotherapies tailored by the genetic makeup of the tumors.
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Affiliation(s)
- Ángel F Álvarez-Prado
- Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, Switzerland; Agora Cancer Research Center, 1011 Lausanne, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
| | - Roeltje R Maas
- Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, Switzerland; Agora Cancer Research Center, 1011 Lausanne, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Klara Soukup
- Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, Switzerland; Agora Cancer Research Center, 1011 Lausanne, Switzerland
| | - Florian Klemm
- Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, Switzerland; Agora Cancer Research Center, 1011 Lausanne, Switzerland
| | - Mara Kornete
- Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, Switzerland; Agora Cancer Research Center, 1011 Lausanne, Switzerland
| | - Fanny S Krebs
- Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Vincent Zoete
- Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Sabina Berezowska
- Department of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Jean-Philippe Brouland
- Department of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Andreas F Hottinger
- Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland; Brain and Spine Tumor Center, Departments of Clinical Neurosciences and Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Roy T Daniel
- L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Monika E Hegi
- L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Johanna A Joyce
- Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, Switzerland; Agora Cancer Research Center, 1011 Lausanne, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
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Zhang L, Jiang Z, Yang X, Qian Y, Wang M, Wu S, Li L, Jia F, Wang Z, Hu Z, Zhao M, Tang X, Li G, Shang H, Chen X, Wang W. A Totipotent "All-In-One" Peptide Sequentially Blocks Immune Checkpoint and Reverses the Immunosuppressive Tumor Microenvironment. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2207330. [PMID: 36259590 DOI: 10.1002/adma.202207330] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/27/2022] [Indexed: 06/16/2023]
Abstract
Immune checkpoint blockade combined with reversal of the immunosuppressive tumor microenvironment (TME) can dramatically enhance anti-tumor immunity, which can be achieved by using multiple-agent therapy. However, the optimal dose and order of administration of different agents remain elusive. To address this dilemma, multiple agents are often grafted together to construct "all-in-one" totipotent drugs, but this usually comes at the cost of a lack of synergy between the agents. Herein, by comprehensively analyzing the conserved sites of the immune checkpoint and TME drug targets, peptide secondary structures, assembly properties, and other physicochemical properties, a high-content peptide library is designed. By using the "3D-molecular-evolution" screening strategy, an efficient and totipotent "all-in-one" peptide (TAP) is obtained, which possesses the abilities of self-assembling, blocking the PD-1/PD-L1 axis, inhibiting Rbm38-eIF4E complex formation, and activating p53. It is shown that in mice treated with TAP, with either subcutaneous tumors or patient-derived xenografts, PD-L1 is blocked, with increased activation of both T and NK cells whilst reversing the immunosuppressive TME. Moreover, TAP can mitigate tumor activity and suppress tumor growth, showing superior therapeutic effect over antibody-based drugs.
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Affiliation(s)
- Limin Zhang
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Key Laboratory of Cluster Science of Ministry of Education, Beijing Key Laboratory of Photoelectronic/Electro-photonic Conversion Materials, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, P. R. China
| | - Zhenqi Jiang
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Key Laboratory of Cluster Science of Ministry of Education, Beijing Key Laboratory of Photoelectronic/Electro-photonic Conversion Materials, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, P. R. China
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, P.R. China
| | - Xi Yang
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Key Laboratory of Cluster Science of Ministry of Education, Beijing Key Laboratory of Photoelectronic/Electro-photonic Conversion Materials, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, P. R. China
- Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P. R. China
| | - Yixia Qian
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P. R. China
| | - Minxuan Wang
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Key Laboratory of Cluster Science of Ministry of Education, Beijing Key Laboratory of Photoelectronic/Electro-photonic Conversion Materials, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, P. R. China
| | - Shang Wu
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Key Laboratory of Cluster Science of Ministry of Education, Beijing Key Laboratory of Photoelectronic/Electro-photonic Conversion Materials, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, P. R. China
| | - Lingyun Li
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Key Laboratory of Cluster Science of Ministry of Education, Beijing Key Laboratory of Photoelectronic/Electro-photonic Conversion Materials, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, P. R. China
| | - Fei Jia
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P. R. China
| | - Zihua Wang
- Centre for Neuroscience Research, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350108, P. R. China
| | - Zhiyuan Hu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P. R. China
| | - Minzhi Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P. R. China
| | - Xiaoying Tang
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Key Laboratory of Cluster Science of Ministry of Education, Beijing Key Laboratory of Photoelectronic/Electro-photonic Conversion Materials, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, P. R. China
| | - Gang Li
- Gastrointestinal Surgery, Shanxi Hospital of Traditional Chinese Medicine, Taiyuan, 030012, P. R. China
| | - Hanbing Shang
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, 200025, P. R. China
| | - Xiaoyuan Chen
- Engineering, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 119074, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
- Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Weizhi Wang
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Key Laboratory of Cluster Science of Ministry of Education, Beijing Key Laboratory of Photoelectronic/Electro-photonic Conversion Materials, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 100081, P. R. China
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dos Reis FD, Jerónimo C, Correia MP. Epigenetic modulation and prostate cancer: Paving the way for NK cell anti-tumor immunity. Front Immunol 2023; 14:1152572. [PMID: 37090711 PMCID: PMC10113550 DOI: 10.3389/fimmu.2023.1152572] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 03/06/2023] [Indexed: 04/25/2023] Open
Abstract
Immunoepigenetics is a growing field, as there is mounting evidence on the key role played by epigenetic mechanisms in the regulation of tumor immune cell recognition and control of immune cell anti-tumor responses. Moreover, it is increasingly acknowledgeable a tie between epigenetic regulation and prostate cancer (PCa) development and progression. PCa is intrinsically a cold tumor, with scarce immune cell infiltration and low inflammatory tumor microenvironment. However, Natural Killer (NK) cells, main anti-tumor effector immune cells, have been frequently linked to improved PCa prognosis. The role that epigenetic-related mechanisms might have in regulating both NK cell recognition of PCa tumor cells and NK cell functions in PCa is still mainly unknown. Epigenetic modulating drugs have been showing boundless therapeutic potential as anti-tumor agents, however their role in immune cell regulation and recognition is scarce. In this review, we focused on studies addressing modulation of epigenetic mechanisms involved in NK cell-mediated responses, including both the epigenetic modulation of tumor cell NK ligand expression and NK cell receptor expression and function in different tumor models, highlighting studies in PCa. The integrated knowledge from diverse epigenetic modulation mechanisms promoting NK cell-mediated immunity in various tumor models might open doors for the development of novel epigenetic-based therapeutic options for PCa management.
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Affiliation(s)
- Filipa D. dos Reis
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Porto, Portugal
- Master Program in Oncology, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Porto, Portugal
- Department of Pathology and Molecular Immunology, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Porto, Portugal
| | - Margareta P. Correia
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Porto, Portugal
- Department of Pathology and Molecular Immunology, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Porto, Portugal
- *Correspondence: Margareta P. Correia,
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ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression. Nat Commun 2022; 13:7281. [PMID: 36435834 PMCID: PMC9701216 DOI: 10.1038/s41467-022-34871-9] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 11/10/2022] [Indexed: 11/28/2022] Open
Abstract
Chronic inflammation and an immunosuppressive microenvironment promote prostate cancer (PCa) progression and diminish the response to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here, we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation-induced IKKβ activation to shape the immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to accelerate prostate tumorigenesis. We identify polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) as the major infiltrating immune cell type that causes immune evasion and reveal that neutralization of PMN-MDSCs restricts the progression of Arid1a-deficient tumors. Mechanistically, inflammatory cues activate IKKβ to phosphorylate ARID1A, leading to its degradation via β-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-κB signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-κB antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKKβ/ARID1A/NF-κB feedback axis integrates inflammation and immunosuppression to promote PCa progression.
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Chen S, Chen X, Zhang P, Chen S, Wang X, Luo Q, Cui Z, Huang Y, Wan L, Hou X, Yao H, Liu X, He A, Jiang Z, Qiu J, Li Y, Yu K, Zhuang J. Bioinformatics Analysis and Experimental Identification of Immune-Related Genes and Immune Cells in the Progression of Retinoblastoma. Invest Ophthalmol Vis Sci 2022; 63:28. [PMID: 36315123 PMCID: PMC9631497 DOI: 10.1167/iovs.63.11.28] [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] [Indexed: 11/16/2022] Open
Abstract
Purpose Retinoblastoma (RB) is the most common type of aggressive intraocular malignancy in children. The alteration of immunity during RB progression and invasion has not yet been well defined. This study investigated significantly altered immune-associated genes and cells related to RB invasion. Methods The differentially expressed immune-related genes (IRGs) in noninvasive RB and invasive RB were identified by analysis of two microarray datasets (GSE97508 and GSE110811). Hub IRGs were further identified by real time PCR. The single-sample gene set enrichment analysis algorithm and Pearson correlation analysis were used to define immune cell infiltration and the relationships between hub IRGs and immune cells. Cell viability and migration were evaluated by CCK-8 and Transwell assays. A xenograft mouse model was used to verify the relationship between Src homology 3 (SH3) domain GRB2-like 2 (SH3GL2) expression and myeloid-derived suppressor cells (MDSCs). Results Eight upregulated genes and six downregulated IRGs were identified in invasive RB. Seven IRGs were confirmed by real-time PCR. Moreover, the proportions of MDSCs were higher in invasive RB tissues than in noninvasive RB tissues. Furthermore, correlation analysis of altered immune genes and cells suggested that SH3GL2, Langerhans cell protein 1 (LCP1) and transmembrane immune signaling adaptor TYROBP have strong connections with MDSCs. Specifically, decreased SH3GL2 expression promoted the migration of RB cells in vitro, increased the tumor size and weight, and increased the numbers of MDSCs in the tumor and spleen in vivo. Conclusions This study indicated that SH3GL2 and MDSCs play a critical role in RB progression and invasion and provide candidate targets for the treatment of RB.
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Affiliation(s)
- Shuilian Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Xi Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Ping Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Shuxia Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Xiao Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Qian Luo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Zedu Cui
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Yuke Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Linxi Wan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Xiangtao Hou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Huan Yao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Xuan Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Anqi He
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Zihua Jiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Jin Qiu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Yan Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Keming Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Jing Zhuang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
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Ding YN, Xue M, Tang QS, Wang LJ, Ding HY, Li H, Gao CC, Yu WP. Immunotherapy-based novel nanoparticles in the treatment of gastrointestinal cancer: Trends and challenges. World J Gastroenterol 2022; 28:5403-5419. [PMID: 36312831 PMCID: PMC9611702 DOI: 10.3748/wjg.v28.i37.5403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/27/2022] [Accepted: 09/15/2022] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal cancer (GIC) is the most common cancer with a poor prognosis. Currently, surgery is the main treatment for GIC. However, the high rate of postoperative recurrence leads to a low five-year survival rate. In recent years, immunotherapy has received much attention. As the only immunotherapy drugs approved by the Food and Drug Administration (FDA), immune checkpoint blockade (ICB) drugs have great potential in cancer therapy. Nevertheless, the efficacy of ICB treatment is greatly limited by the low immunogenicity and immunosuppressive microenvironment of GIC. Therefore, the targets of immunotherapy have expanded from ICB to increasing tumor immunogenicity, increasing the recruitment and maturation of immune cells and reducing the proportion of inhibitory immune cells, such as M2-like macrophages, regulatory T cells and myeloid-derived suppressor cells. Moreover, with the development of nanotechnology, a variety of nanoparticles have been approved by the FDA for clinical therapy, so novel nanodrug delivery systems have become a research focus for anticancer therapy. In this review, we summarize recent advances in the application of immunotherapy-based nanoparticles in GICs, such as gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic cancer, and described the existing challenges and future trends.
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Affiliation(s)
- Yi-Nan Ding
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Ming Xue
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Qiu-Sha Tang
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Li-Jun Wang
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Hui-Yan Ding
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Han Li
- Department of Tuberculosis, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Cheng-Cheng Gao
- Department of Radiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Wei-Ping Yu
- Medical School, Southeast University, Nanjing 210009, Jiangsu Province, China
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Rappold PM, Vuong L, Leibold J, Chakiryan NH, Curry M, Kuo F, Sabio E, Jiang H, Nixon BG, Liu M, Berglund AE, Silagy AW, Mascareno A, Golkaram M, Marker M, Reising A, Savchenko A, Millholland J, Chen YB, Russo P, Coleman J, Reznik E, Manley BJ, Ostrovnaya I, Makarov V, DiNatale RG, Blum KA, Ma X, Chowell D, Li MO, Solit DB, Lowe SW, Chan TA, Motzer RJ, Voss MH, Hakimi AA. A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma. Cancer Discov 2022; 12:2308-2329. [PMID: 35758895 PMCID: PMC9720541 DOI: 10.1158/2159-8290.cd-21-0925] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 04/22/2022] [Accepted: 06/22/2022] [Indexed: 11/16/2022]
Abstract
It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC. SIGNIFICANCE Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model. This article is highlighted in the In This Issue feature, p. 2221.
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Affiliation(s)
- Phillip M. Rappold
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Lynda Vuong
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA
| | - Josef Leibold
- Cancer Biology and Genetics Program, MSKCC, New York, NY, USA
- Department of Medical Oncology & Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen 72076, Germany
- DFG Cluster of Excellence 2180 Image-Guided and Functional Instructed Tumor Therapy (iFIT), University of Tuebingen, Tuebingen 72076, Germany
| | - Nicholas H. Chakiryan
- Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Michael Curry
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Fengshen Kuo
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA
| | - Erich Sabio
- Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA
| | - Hui Jiang
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA
| | - Briana G. Nixon
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ming Liu
- Legend Biotech USA Inc, NJ, USA
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anders E. Berglund
- Department of Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Andrew W. Silagy
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ankur Mascareno
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA
| | - Mahdi Golkaram
- Illumina, Inc., 5200 Illumina Way, San Diego, CA 92122, USA
| | | | | | | | | | | | - Paul Russo
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jonathan Coleman
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ed Reznik
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Brandon J. Manley
- Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Irina Ostrovnaya
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vladimir Makarov
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA
| | - Renzo G. DiNatale
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kyle A. Blum
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Xiaoxiao Ma
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA
| | - Diego Chowell
- Department of Oncological Sciences, The Precision Immunology Institute, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ming O. Li
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David B. Solit
- Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, MSKCC, New York, NY, USA
| | - Scott W. Lowe
- Cancer Biology and Genetics Program, MSKCC, New York, NY, USA
| | - Timothy A. Chan
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA
| | - Robert J. Motzer
- Department of Medicine, Genitourinary Oncology, MSKCC, New York, NY, USA
| | - Martin H. Voss
- Department of Medicine, Genitourinary Oncology, MSKCC, New York, NY, USA
| | - A. Ari Hakimi
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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So JY, Ohm J, Lipkowitz S, Yang L. Triple negative breast cancer (TNBC): Non-genetic tumor heterogeneity and immune microenvironment: Emerging treatment options. Pharmacol Ther 2022; 237:108253. [PMID: 35872332 PMCID: PMC9378710 DOI: 10.1016/j.pharmthera.2022.108253] [Citation(s) in RCA: 110] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/01/2022] [Accepted: 07/18/2022] [Indexed: 12/17/2022]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by extensive intra-tumoral heterogeneity, and frequently develops resistance to therapies. Tumor heterogeneity and lack of biomarkers are thought to be some of the most difficult challenges driving therapeutic resistance and relapse. This review will summarize current therapy for TNBC, studies in treatment resistance and relapse, including data from recent single cell sequencing. We will discuss changes in both the transcriptome and epigenome of TNBC, and we will review mechanisms regulating the immune microenvironment. Lastly, we will provide new perspective in patient stratification, and treatment options targeting transcriptome dysregulation and the immune microenvironment of TNBC patients.
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Affiliation(s)
- Jae Young So
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Joyce Ohm
- Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Stan Lipkowitz
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Li Yang
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Li F, Cai J, Liu J, Yu SC, Zhang X, Su Y, Gao L. Construction of a solid Cox model for AML patients based on multiomics bioinformatic analysis. Front Oncol 2022; 12:925615. [PMID: 36033493 PMCID: PMC9399435 DOI: 10.3389/fonc.2022.925615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy. The bone marrow (BM) microenvironment in AML plays an important role in leukemogenesis, drug resistance and leukemia relapse. In this study, we aimed to identify reliable immune-related biomarkers for AML prognosis by multiomics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and constructed a LASSO-Cox regression model to predict the prognosis of AML using multiomics bioinformatic analysis data. This was followed by independent validation of the model in the GSE106291 (n=251) data set and mutated genes in clinical samples for predicting overall survival (OS). Molecular docking was performed to predict the most optimal ligands to the genes in prognostic model. The single-cell RNA sequence dataset GSE116256 was used to clarify the expression of the hub genes in different immune cell types. According to their significant differences in immune gene signatures and survival trends, we concluded that the immune infiltration-lacking subtype (IL type) is associated with better prognosis than the immune infiltration-rich subtype (IR type). Using the LASSO model, we built a classifier based on 5 hub genes to predict the prognosis of AML (risk score = -0.086×ADAMTS3 + 0.180×CD52 + 0.472×CLCN5 - 0.356×HAL + 0.368×ICAM3). In summary, we constructed a prognostic model of AML using integrated multiomics bioinformatic analysis that could serve as a therapeutic classifier.
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Affiliation(s)
- Fu Li
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jiao Cai
- Department of Hematology and Hematopoietic Stem Cell Transplantation Centre, The General Hospital of Western Theater Command, Chengdu, China
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Army Medical University, Chongqing, China
| | - Jia Liu
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Shi-cang Yu
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Army Medical University, Chongqing, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yi Su
- Department of Hematology and Hematopoietic Stem Cell Transplantation Centre, The General Hospital of Western Theater Command, Chengdu, China
- *Correspondence: Lei Gao, ; Yi Su,
| | - Lei Gao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
- *Correspondence: Lei Gao, ; Yi Su,
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Chen Y, Yang S, Tavormina J, Tampe D, Zeisberg M, Wang H, Mahadevan KK, Wu CJ, Sugimoto H, Chang CC, Jenq RR, McAndrews KM, Kalluri R. Oncogenic collagen I homotrimers from cancer cells bind to α3β1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer. Cancer Cell 2022; 40:818-834.e9. [PMID: 35868307 PMCID: PMC9831277 DOI: 10.1016/j.ccell.2022.06.011] [Citation(s) in RCA: 137] [Impact Index Per Article: 45.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 03/14/2022] [Accepted: 06/27/2022] [Indexed: 01/12/2023]
Abstract
In contrast to normal type I collagen (Col1) heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (α1/α1/α1). Col1 homotrimer results from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via α3β1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Col1 homotrimers increases overall survival of mice with pancreatic ductal adenocarcinoma (PDAC), associated with reprograming of the tumor microbiome with increased microaerophilic Campylobacterales, which can be reversed with broad-spectrum antibiotics. Deletion of Col1 homotrimers enhances T cell infiltration and enables efficacy of anti-PD-1 immunotherapy. This study identifies the functional impact of Col1 homotrimers on tumor microbiome and tumor immunity, implicating Col1 homotrimer-α3β1 integrin signaling axis as a cancer-specific therapeutic target.
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Affiliation(s)
- Yang Chen
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Sujuan Yang
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Jena Tavormina
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Desiree Tampe
- Department of Nephrology and Rheumatology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | - Michael Zeisberg
- Department of Nephrology and Rheumatology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | - Huamin Wang
- Department of Anatomical Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Krishnan K Mahadevan
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Chang-Jiun Wu
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Hikaru Sugimoto
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Chia-Chi Chang
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Robert R Jenq
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Kathleen M McAndrews
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Raghu Kalluri
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; James P. Allison Institute, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Bioengineering, Rice University, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
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50
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Co-dependencies in the tumor immune microenvironment. Oncogene 2022; 41:3821-3829. [PMID: 35817840 PMCID: PMC9893036 DOI: 10.1038/s41388-022-02406-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 02/04/2023]
Abstract
Activated oncogenes and disrupted tumor suppressor genes (TSGs) not only endow aspiring cancer cells with new biological capabilities but also influence the composition and function of host cells in the tumor microenvironment (TME). These non-cancer host cells can in turn provide cancer cells with growth support and protection from the anti-tumor immune response. In this ecosystem, geospatially heterogenous "subTME" adds to the complexity of the "global" TME which bestows tumors with increased tumorigenic ability and resistance to therapy. This review highlights how specific genetic alterations in cancer cells establish various symbiotic co-dependencies with surrounding host cells and details the cooperative role of the host cells in tumor biology. These essential interactions expand the repertoire of targets for the development of precision cancer treatments.
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