Successful immunotherapy relies on both intratumoral and systemic immunity, which is yet to be achieved for most patients with cancer. Here, we identify P4HA1, encoding prolyl 4-hydroxylase 1, as a crucial regulator of CD8+ T cell differentiation strongly upregulated in tumor-draining lymph nodes (TDLNs) and hypoxic tumor microenvironment. P4HA1 accumulates in mitochondria, disrupting the tricarboxylic acid (TCA) cycle through aberrant α-ketoglutarate and succinate metabolism, promoting mitochondria unfitness and exhaustion while suppressing progenitor expansion. Targeting P4HA1 enhances both adoptive and endogenous TCF1+ CD8+ T progenitor expansion while mitigating the development of exhaustion in the tumor, TDLN, and blood, enabling a notable and durable systemic anti-cancer immunity. We propose that P4HA1 induction in CD8+ T cells in cancer orchestrates an immune-escape program, offering a T cell-directed target for system immunotherapy in solid tumors.
{"title":"Targeting P4HA1 promotes CD8+ T cell progenitor expansion toward immune memory and systemic anti-tumor immunity","authors":"Shijun Ma, Li-Teng Ong, Zemin Jiang, Wee Chyan Lee, Puay Leng Lee, Mubaraka Yusuf, Henrik J. Ditzel, Yulan Wang, Qingfeng Chen, Wenyu Wang, Xiaojian Wu, Ern Yu Tan, Qiang Yu","doi":"10.1016/j.ccell.2024.12.001","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.12.001","url":null,"abstract":"Successful immunotherapy relies on both intratumoral and systemic immunity, which is yet to be achieved for most patients with cancer. Here, we identify <em>P4HA1</em>, encoding prolyl 4-hydroxylase 1, as a crucial regulator of CD8<sup>+</sup> T cell differentiation strongly upregulated in tumor-draining lymph nodes (TDLNs) and hypoxic tumor microenvironment. P4HA1 accumulates in mitochondria, disrupting the tricarboxylic acid (TCA) cycle through aberrant α-ketoglutarate and succinate metabolism, promoting mitochondria unfitness and exhaustion while suppressing progenitor expansion. Targeting P4HA1 enhances both adoptive and endogenous TCF1<sup>+</sup> CD8<sup>+</sup> T progenitor expansion while mitigating the development of exhaustion in the tumor, TDLN, and blood, enabling a notable and durable systemic anti-cancer immunity. We propose that P4HA1 induction in CD8<sup>+</sup> T cells in cancer orchestrates an immune-escape program, offering a T cell-directed target for system immunotherapy in solid tumors.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"33 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-12DOI: 10.1016/j.ccell.2024.11.011
Courtney T. Kureshi, Stephanie K. Dougan
Cytokines are proteins used by immune cells to communicate with each other and with cells in their environment. The pleiotropic effects of cytokine networks are determined by which cells express cytokines and which cells express cytokine receptors, with downstream outcomes that can differ based on cell type and environmental cues. Certain cytokines, such as interferon (IFN)-γ, have been clearly linked to anti-tumor immunity, while others, such as the innate inflammatory cytokines, promote oncogenesis. Here we provide an overview of the functional roles of cytokines in the tumor microenvironment. Although we have a sophisticated understanding of cytokine networks, therapeutically targeting cytokine pathways in cancer has been challenging. We discuss current progress in cytokine blockade, cytokine-based therapies, and engineered cytokine therapeutics as emerging cancer treatments of interest.
{"title":"Cytokines in cancer","authors":"Courtney T. Kureshi, Stephanie K. Dougan","doi":"10.1016/j.ccell.2024.11.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.011","url":null,"abstract":"Cytokines are proteins used by immune cells to communicate with each other and with cells in their environment. The pleiotropic effects of cytokine networks are determined by which cells express cytokines and which cells express cytokine receptors, with downstream outcomes that can differ based on cell type and environmental cues. Certain cytokines, such as interferon (IFN)-γ, have been clearly linked to anti-tumor immunity, while others, such as the innate inflammatory cytokines, promote oncogenesis. Here we provide an overview of the functional roles of cytokines in the tumor microenvironment. Although we have a sophisticated understanding of cytokine networks, therapeutically targeting cytokine pathways in cancer has been challenging. We discuss current progress in cytokine blockade, cytokine-based therapies, and engineered cytokine therapeutics as emerging cancer treatments of interest.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"4 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-12DOI: 10.1016/j.ccell.2024.11.008
Zhen Yang, Xinpeng Liu, Jun Zhu, Yangyang Chai, Boyi Cong, Bo Li, Wanfeng Gao, Ye Hu, Mingyue Wen, Yanfang Liu, Li Fu, Xuetao Cao
Deciphering mechanisms for cancer immune escape may provide targets for improving immunotherapy efficacy. By in vivo genome-wide CRISPR loss-of-function screening in a mouse model of triple negative breast cancer (TNBC), we uncovered a non-classical function of Cd28 in cancer cells to promote immune escape. Knocking out Cd28 in cancer cells increased infiltration of type I conventional DC (cDC1) and activated tumor-specific CD8+ T cells, and pharmaceutical inducible knockdown of Cd28 inhibited pre-established tumor growth and overcame anti-PD-1 resistance in vivo. Furthermore, high expression of cancer cell CD28 in human TNBC tissues correlated with elevated PD-L1 expression, less CD8+ T cell infiltration, and poor prognosis. Mechanistically, intracellular CD28 directly bound to Cd274 mRNA and recruited spliceosomal factor SNRPB2 to stabilize Cd274 mRNA in nucleus, promoting PD-L1 expression and immune escape. Therefore, disrupting cancer cell CD28-mediated immune escape may provide a potential approach to improve breast cancer immunotherapy.
{"title":"Inhibiting intracellular CD28 in cancer cells enhances antitumor immunity and overcomes anti-PD-1 resistance via targeting PD-L1","authors":"Zhen Yang, Xinpeng Liu, Jun Zhu, Yangyang Chai, Boyi Cong, Bo Li, Wanfeng Gao, Ye Hu, Mingyue Wen, Yanfang Liu, Li Fu, Xuetao Cao","doi":"10.1016/j.ccell.2024.11.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.008","url":null,"abstract":"Deciphering mechanisms for cancer immune escape may provide targets for improving immunotherapy efficacy. By <em>in vivo</em> genome-wide CRISPR loss-of-function screening in a mouse model of triple negative breast cancer (TNBC), we uncovered a non-classical function of <em>Cd28</em> in cancer cells to promote immune escape. Knocking out <em>Cd28</em> in cancer cells increased infiltration of type I conventional DC (cDC1) and activated tumor-specific CD8<sup>+</sup> T cells, and pharmaceutical inducible knockdown of <em>Cd28</em> inhibited pre-established tumor growth and overcame anti-PD-1 resistance <em>in vivo</em>. Furthermore, high expression of cancer cell CD28 in human TNBC tissues correlated with elevated PD-L1 expression, less CD8<sup>+</sup> T cell infiltration, and poor prognosis. Mechanistically, intracellular CD28 directly bound to <em>Cd274</em> mRNA and recruited spliceosomal factor SNRPB2 to stabilize <em>Cd274</em> mRNA in nucleus, promoting PD-L1 expression and immune escape. Therefore, disrupting cancer cell CD28-mediated immune escape may provide a potential approach to improve breast cancer immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"22 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-12DOI: 10.1016/j.ccell.2024.11.010
Yan-Ruide Li, Kuangyi Zhou, Yichen Zhu, Tyler Halladay, Lili Yang
Unconventional T cells, including invariant natural killer T (iNKT) cells, gamma delta (γδ) T cells, and mucosal-associated invariant T (MAIT) cells, play important roles in both innate and adaptive immunity. These cells respond to tumors rapidly and influence the tumor microenvironment (TME). Recent advances in understanding their biology, as well as the development of novel therapeutic approaches, have underscored their potential in cancer immunotherapy. This commentary will assess these advances and translational possibilities in the field.
{"title":"Breaking the mold: Unconventional T cells in cancer therapy","authors":"Yan-Ruide Li, Kuangyi Zhou, Yichen Zhu, Tyler Halladay, Lili Yang","doi":"10.1016/j.ccell.2024.11.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.010","url":null,"abstract":"Unconventional T cells, including invariant natural killer T (iNKT) cells, gamma delta (γδ) T cells, and mucosal-associated invariant T (MAIT) cells, play important roles in both innate and adaptive immunity. These cells respond to tumors rapidly and influence the tumor microenvironment (TME). Recent advances in understanding their biology, as well as the development of novel therapeutic approaches, have underscored their potential in cancer immunotherapy. This commentary will assess these advances and translational possibilities in the field.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"62 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-12DOI: 10.1016/j.ccell.2024.11.014
Christina M. Scheffler, Paul A. Beavis, Phillip K. Darcy
In this issue of Cancer Cell, Qiu et al. use single-cell metabolic analysis to identify reduced mannose metabolism as a previously unknown feature of exhausted T cells. This metabolic pathway can be targeted to enhance memory and persistence of adoptively transferred T cells, resulting in improved anti-tumor efficacy.
{"title":"A metabolic pathway for improving adoptive cellular therapy","authors":"Christina M. Scheffler, Paul A. Beavis, Phillip K. Darcy","doi":"10.1016/j.ccell.2024.11.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.014","url":null,"abstract":"In this issue of <em>Cancer Cell</em>, Qiu et al. use single-cell metabolic analysis to identify reduced mannose metabolism as a previously unknown feature of exhausted T cells. This metabolic pathway can be targeted to enhance memory and persistence of adoptively transferred T cells, resulting in improved anti-tumor efficacy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"10 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-12DOI: 10.1016/j.ccell.2024.11.009
Catherine Alix-Panabières, Klaus Pantel
Liquid biopsy has received tremendous attention as a non-invasive approach for detecting and tracking cancer. Here, we discuss the latest work on circulating tumor DNA and circulating tumor cells with respect to clinical applications, including cancer screening, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms.
{"title":"Advances in liquid biopsy: From exploration to practical application","authors":"Catherine Alix-Panabières, Klaus Pantel","doi":"10.1016/j.ccell.2024.11.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.009","url":null,"abstract":"Liquid biopsy has received tremendous attention as a non-invasive approach for detecting and tracking cancer. Here, we discuss the latest work on circulating tumor DNA and circulating tumor cells with respect to clinical applications, including cancer screening, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"239 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-12DOI: 10.1016/j.ccell.2024.11.012
Maria F. Gonzalez-Aponte, Anna R. Damato, Tatiana Simon, Nigina Aripova, Fabrizio Darby, Myung Sik Jeon, Jingqin Luo, Joshua B. Rubin, Erik D. Herzog
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis despite aggressive therapy. Here, we hypothesized that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We find daily glucocorticoids promote or suppress GBM growth through glucocorticoid receptor (GR) signaling depending on time of day and the clock genes, Bmal1 and Cry. Blocking circadian signals, like vasoactive intestinal peptide or glucocorticoids, dramatically slows GBM growth and disease progression. Analysis of human GBM samples from The Cancer Genome Atlas (TCGA) shows that high GR expression significantly increases hazard of mortality. Finally, mouse and human GBM models have intrinsic circadian rhythms in clock gene expression in vitro and in vivo that entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We conclude that GBM entrains to the circadian circuit of the brain, modulating its growth through clock-controlled cues, like glucocorticoids.
{"title":"Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host","authors":"Maria F. Gonzalez-Aponte, Anna R. Damato, Tatiana Simon, Nigina Aripova, Fabrizio Darby, Myung Sik Jeon, Jingqin Luo, Joshua B. Rubin, Erik D. Herzog","doi":"10.1016/j.ccell.2024.11.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.012","url":null,"abstract":"Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis despite aggressive therapy. Here, we hypothesized that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We find daily glucocorticoids promote or suppress GBM growth through glucocorticoid receptor (GR) signaling depending on time of day and the clock genes, <em>Bmal1</em> and <em>Cry</em>. Blocking circadian signals, like vasoactive intestinal peptide or glucocorticoids, dramatically slows GBM growth and disease progression. Analysis of human GBM samples from The Cancer Genome Atlas (TCGA) shows that high GR expression significantly increases hazard of mortality. Finally, mouse and human GBM models have intrinsic circadian rhythms in clock gene expression <em>in vitro</em> and <em>in vivo</em> that entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We conclude that GBM entrains to the circadian circuit of the brain, modulating its growth through clock-controlled cues, like glucocorticoids.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"24 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-12DOI: 10.1016/j.ccell.2024.11.004
Katja A. Lamia
Circadian disruption increases cancer risk, but connections between circadian clocks and cancer biology are diverse and depend on tumor type. In this issue of Cancer Cell, Gonzalez-Aponte et al. demonstrate that circadian timing of glucocorticoid exposure affects glioblastoma growth. These findings underscore the importance of timing in designing therapeutic interventions.
{"title":"Stressing the importance of circadian time in treatment responses","authors":"Katja A. Lamia","doi":"10.1016/j.ccell.2024.11.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.004","url":null,"abstract":"Circadian disruption increases cancer risk, but connections between circadian clocks and cancer biology are diverse and depend on tumor type. In this issue of <em>Cancer Cell</em>, Gonzalez-Aponte et al. demonstrate that circadian timing of glucocorticoid exposure affects glioblastoma growth. These findings underscore the importance of timing in designing therapeutic interventions.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"50 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-12DOI: 10.1016/j.ccell.2024.11.013
Heehwa G. Son, Dat Thinh Ha, Yun Xia, Tiancheng Li, Jasmine Blandin, Tomonori Oka, Marjan Azin, Danielle N. Conrad, Can Zhou, Yuhan Zeng, Tatsuya Hasegawa, John D. Strickley, Jonathan L. Messerschmidt, Ranya Guennoun, Tal H. Erlich, Gregory L. Shoemaker, Luke H. Johnson, Kenneth E. Palmer, David E. Fisher, Thomas D. Horn, Shadmehr Demehri
Immunosuppression commonly disrupts the homeostasis of mutated normal skin, leading to widespread skin dysplasia and field cancerization. However, the immune system’s role in maintaining the normal state of mutated tissues remains uncertain. Herein, we demonstrate that T cell immunity to cutaneotropic papillomaviruses promotes the homeostasis of ultraviolet radiation-damaged skin. Mouse papillomavirus (MmuPV1) colonization blocks the expansion of mutant p53 clones in the epidermis in a CD8+ T cell-dependent manner. MmuPV1 activity is increased in p53-deficient keratinocytes, leading to their specific targeting by CD8+ T cells in the skin. Sun-exposed human skin containing mutant p53 clones shows increased epidermal beta-human papillomavirus (β-HPV) activity and CD8+ T cell infiltrates compared with sun-protected skin. The expansion of mutant p53 clones in premalignant skin lesions associates with β-HPV loss. Thus, immunity to commensal HPVs contributes to the homeostasis of mutated normal skin, highlighting the role of virome-immune system interactions in preserving aging human tissues.
{"title":"Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin","authors":"Heehwa G. Son, Dat Thinh Ha, Yun Xia, Tiancheng Li, Jasmine Blandin, Tomonori Oka, Marjan Azin, Danielle N. Conrad, Can Zhou, Yuhan Zeng, Tatsuya Hasegawa, John D. Strickley, Jonathan L. Messerschmidt, Ranya Guennoun, Tal H. Erlich, Gregory L. Shoemaker, Luke H. Johnson, Kenneth E. Palmer, David E. Fisher, Thomas D. Horn, Shadmehr Demehri","doi":"10.1016/j.ccell.2024.11.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.013","url":null,"abstract":"Immunosuppression commonly disrupts the homeostasis of mutated normal skin, leading to widespread skin dysplasia and field cancerization. However, the immune system’s role in maintaining the normal state of mutated tissues remains uncertain. Herein, we demonstrate that T cell immunity to cutaneotropic papillomaviruses promotes the homeostasis of ultraviolet radiation-damaged skin. Mouse papillomavirus (MmuPV1) colonization blocks the expansion of mutant p53 clones in the epidermis in a CD8<sup>+</sup> T cell-dependent manner. MmuPV1 activity is increased in p53-deficient keratinocytes, leading to their specific targeting by CD8<sup>+</sup> T cells in the skin. Sun-exposed human skin containing mutant p53 clones shows increased epidermal beta-human papillomavirus (β-HPV) activity and CD8<sup>+</sup> T cell infiltrates compared with sun-protected skin. The expansion of mutant p53 clones in premalignant skin lesions associates with β-HPV loss. Thus, immunity to commensal HPVs contributes to the homeostasis of mutated normal skin, highlighting the role of virome-immune system interactions in preserving aging human tissues.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"58 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1016/j.ccell.2024.11.005
Inga-Maria Launonen, Iga Niemiec, María Hincapié-Otero, Erdogan Pekcan Erkan, Ada Junquera, Daria Afenteva, Matias M. Falco, Zhihan Liang, Matilda Salko, Foteini Chamchougia, Angela Szabo, Fernando Perez-Villatoro, Yilin Li, Giulia Micoli, Ashwini Nagaraj, Ulla-Maija Haltia, Essi Kahelin, Jaana Oikkonen, Johanna Hynninen, Anni Virtanen, Anniina Färkkilä
Anti-tumor immunity is crucial for high-grade serous ovarian cancer (HGSC) prognosis, yet its adaptation upon standard chemotherapy remains poorly understood. Here, we conduct spatial and molecular characterization of 117 HGSC samples collected before and after chemotherapy. Our single-cell and spatial analyses reveal increasingly versatile immune cell states forming spatiotemporally dynamic microcommunities. We describe Myelonets, networks of interconnected myeloid cells that contribute to CD8+ T cell exhaustion post-chemotherapy and show that M1/M2 polarization at the tumor-stroma interface is associated with CD8+ T cell exhaustion and exclusion, correlating with poor chemoresponse. Single-cell and spatial transcriptomics reveal prominent myeloid-T cell interactions via NECTIN2-TIGIT induced by chemotherapy. Targeting these interactions using a functional patient-derived immuno-oncology platform demonstrates that high NECTIN2-TIGIT signaling in matched tumors predicts responses to immune checkpoint blockade. Our discovery of clinically relevant myeloid-driven spatial T cell exhaustion unlocks immunotherapeutic strategies to unleash CD8+ T cell-mediated anti-tumor immunity in HGSC.
{"title":"Chemotherapy induces myeloid-driven spatially confined T cell exhaustion in ovarian cancer","authors":"Inga-Maria Launonen, Iga Niemiec, María Hincapié-Otero, Erdogan Pekcan Erkan, Ada Junquera, Daria Afenteva, Matias M. Falco, Zhihan Liang, Matilda Salko, Foteini Chamchougia, Angela Szabo, Fernando Perez-Villatoro, Yilin Li, Giulia Micoli, Ashwini Nagaraj, Ulla-Maija Haltia, Essi Kahelin, Jaana Oikkonen, Johanna Hynninen, Anni Virtanen, Anniina Färkkilä","doi":"10.1016/j.ccell.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.005","url":null,"abstract":"Anti-tumor immunity is crucial for high-grade serous ovarian cancer (HGSC) prognosis, yet its adaptation upon standard chemotherapy remains poorly understood. Here, we conduct spatial and molecular characterization of 117 HGSC samples collected before and after chemotherapy. Our single-cell and spatial analyses reveal increasingly versatile immune cell states forming spatiotemporally dynamic microcommunities. We describe Myelonets, networks of interconnected myeloid cells that contribute to CD8<sup>+</sup> T cell exhaustion post-chemotherapy and show that M1/M2 polarization at the tumor-stroma interface is associated with CD8<sup>+</sup> T cell exhaustion and exclusion, correlating with poor chemoresponse. Single-cell and spatial transcriptomics reveal prominent myeloid-T cell interactions via NECTIN2-TIGIT induced by chemotherapy. Targeting these interactions using a functional patient-derived immuno-oncology platform demonstrates that high NECTIN2-TIGIT signaling in matched tumors predicts responses to immune checkpoint blockade. Our discovery of clinically relevant myeloid-driven spatial T cell exhaustion unlocks immunotherapeutic strategies to unleash CD8<sup>+</sup> T cell-mediated anti-tumor immunity in HGSC.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"95 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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