Cancer CellPub Date : 2025-02-20DOI: 10.1016/j.ccell.2025.01.013
Patrizia Porazzi, Siena Nason, Ziqi Yang, Alberto Carturan, Guido Ghilardi, Puneeth Guruprasad, Ruchi P. Patel, Melody Tan, Anushka Anant Padmanabhan, Jean Lemoine, Eugenio Fardella, Yunlin Zhang, Raymone Pajarillo, Linhui Chen, Ositadimma Ugwuanyi, Kelly Markowitz, Devora Delman, Mathew G. Angelos, Olga Shestova, Yusuke Isshiki, Marco Ruella
{"title":"EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models","authors":"Patrizia Porazzi, Siena Nason, Ziqi Yang, Alberto Carturan, Guido Ghilardi, Puneeth Guruprasad, Ruchi P. Patel, Melody Tan, Anushka Anant Padmanabhan, Jean Lemoine, Eugenio Fardella, Yunlin Zhang, Raymone Pajarillo, Linhui Chen, Ositadimma Ugwuanyi, Kelly Markowitz, Devora Delman, Mathew G. Angelos, Olga Shestova, Yusuke Isshiki, Marco Ruella","doi":"10.1016/j.ccell.2025.01.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.013","url":null,"abstract":"Tumor resistance to chimeric antigen receptor T cell (CAR-T) and, in general, to adoptive cell immunotherapies (ACTs) is a major challenge in the clinic. We hypothesized that inhibiting the tumor drivers’ methyltransferases EZH2 and EZH1 could enhance ACT by rewiring cancer cells to a more immunogenic state. In human B cell lymphoma, EZH2 inhibition (tazemetostat) improved the efficacy of anti-CD19 CAR-T by enhancing activation, expansion, and tumor infiltration. Mechanistically, tazemetostat-treated tumors showed upregulation of genes related to adhesion, B cell activation, and inflammatory responses, and increased avidity to CAR-T. Furthermore, tazemetostat improved CAR- and TCR-engineered T cell efficacy in multiple liquid (myeloma and acute myeloid leukemia) and solid (sarcoma, ovarian, and prostate) cancers. Lastly, combined EZH1/EZH2 inhibition (valemetostat) further boosted CAR-T efficacy and expansion in multiple cancers. This study shows that EZH1/2 inhibition reprograms tumors to a more immunogenic state and potentiates ACT in preclinical models of both liquid and solid cancers.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"17 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451884","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}
Cancer CellPub Date : 2025-02-20DOI: 10.1016/j.ccell.2025.01.012
Haiquan Chen, Chaoqiang Deng, Jian Gao, Jun Wang, Fangqiu Fu, Yue Wang, Qiming Wang, Mou Zhang, Shiyue Zhang, Fanfan Fan, Kun Liu, Bo Yang, Qiming He, Qiang Zheng, Xuxia Shen, Jin Wang, Tao Hu, Changbin Zhu, Fei Yang, Yonghong He, Zhiwei Cao
{"title":"Integrative spatial analysis reveals tumor heterogeneity and immune colony niche related to clinical outcomes in small cell lung cancer","authors":"Haiquan Chen, Chaoqiang Deng, Jian Gao, Jun Wang, Fangqiu Fu, Yue Wang, Qiming Wang, Mou Zhang, Shiyue Zhang, Fanfan Fan, Kun Liu, Bo Yang, Qiming He, Qiang Zheng, Xuxia Shen, Jin Wang, Tao Hu, Changbin Zhu, Fei Yang, Yonghong He, Zhiwei Cao","doi":"10.1016/j.ccell.2025.01.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.012","url":null,"abstract":"Recent advances have shed light on the molecular heterogeneity of small cell lung cancer (SCLC), yet the spatial organizations and cellular interactions in tumor immune microenvironment remain to be elucidated. Here, we employ co-detection by indexing (CODEX) and multi-omics profiling to delineate the spatial landscape for 165 SCLC patients, generating 267 high-dimensional images encompassing over 9.3 million cells. Integrating CODEX and genomic data reveals a multi-positive tumor cell neighborhood within ASCL1<sup>+</sup> (SCLC-A) subtype, characterized by high SLFN11 expression and associated with poor prognosis. We further develop a cell colony detection algorithm (ColonyMap) and reveal a spatially assembled immune niche consisting of antitumoral macrophages, CD8<sup>+</sup> T cells and natural killer T cells (MT<sup>2</sup>) which highly correlates with superior survival and predicts improving immunotherapy response in an independent cohort. This study serves as a valuable resource to study SCLC spatial heterogeneity and offers insights into potential patient stratification and personalized treatments.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"11 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451888","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}
Cancer CellPub Date : 2025-02-10DOI: 10.1016/j.ccell.2025.01.005
Lorenzo Galluzzi, Emma Guilbaud, Abhishek D. Garg
{"title":"Mitochondrial succinate feeds T cell exhaustion in cancer","authors":"Lorenzo Galluzzi, Emma Guilbaud, Abhishek D. Garg","doi":"10.1016/j.ccell.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.005","url":null,"abstract":"Mitochondrial fitness is critical for effector CD8<sup>+</sup> T cell responses against cancer. In this issue of <em>Cancer Cell</em>, Ma et al. delineate a novel mechanism linking defects in mitochondrial metabolism as elicited by prolyl 4-hydroxylase subunit alpha 1 (P4HA1) to T cell exhaustion and reduced tumor sensitivity to immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"12 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375419","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}
{"title":"Immunosensitivity cuts across mismatch repair status in colorectal cancer","authors":"Allyson Moraig Peddle, Gertjan Rasschaert, Sabine Tejpar","doi":"10.1016/j.ccell.2025.01.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.010","url":null,"abstract":"In this issue of <em>Cancer Cell</em>, Acha-Sagredo et al. reveal an interferon-high immunophenotype in colorectal cancer that predicts responsiveness to immune checkpoint inhibitors across both mismatch repair-deficient and mismatch repair-proficient subtypes. They identify CD74 as a biomarker and establish the importance of epithelial interferon levels in regulating immune responses.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"144 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375421","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}
Cancer CellPub Date : 2025-02-10DOI: 10.1016/j.ccell.2025.01.009
Julia Schiantarelli, Mouadh Benamar, Jihye Park, Haley E. Sax, Giacomo Oliveira, Alice Bosma-Moody, Katie M. Campbell, David Liu, Douglas B. Johnson, Scott Rodig, Catherine J. Wu, F. Stephen Hodi, Antoni Ribas, Eliezer Van Allen, Rizwan Haq
{"title":"Genomic mediators of acquired resistance to immunotherapy in metastatic melanoma","authors":"Julia Schiantarelli, Mouadh Benamar, Jihye Park, Haley E. Sax, Giacomo Oliveira, Alice Bosma-Moody, Katie M. Campbell, David Liu, Douglas B. Johnson, Scott Rodig, Catherine J. Wu, F. Stephen Hodi, Antoni Ribas, Eliezer Van Allen, Rizwan Haq","doi":"10.1016/j.ccell.2025.01.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.009","url":null,"abstract":"Although some patients with metastatic melanoma experience durable responses to immune checkpoint inhibitors (ICIs), most exhibit intrinsic or acquired resistance to these therapies. Here, we compare somatic genomic profiles from matched pre-treatment and post-resistance tumor biopsies in patients (<em>n</em> = 25) with metastatic melanoma who exhibited heterogeneous ICI responses to nominate additional mediators of acquired resistance. We find that several acquired resistance tumors exhibit defects in <em>B2M</em> or <em>JAK1/2</em>, consistent with prior findings. We also discover resistance-associated mutations in <em>SEC24C</em> and <em>SEC24D</em> in 3 patients. SEC24 has an essential role in the trafficking of the dsDNA sensor STING and has been linked to interferonopathies. Melanoma cells engineered to express the <em>SEC24C</em> mutations observed in patients exhibit diminished STING signaling, including decreased type I interferon production, antigen presentation, and a reduced capacity to activate cytotoxic T cells. This study nominates a role for aberrant STING trafficking in acquired resistance to ICIs.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"26 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375425","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}
Cancer CellPub Date : 2025-02-10DOI: 10.1016/j.ccell.2025.01.004
Lukas M. Braun, Sophie Giesler, Geoffroy Andrieux, Roxane Riemer, Nana Talvard-Balland, Sandra Duquesne, Tamina Rückert, Susanne Unger, Stefanie Kreutmair, Melissa Zwick, Marie Follo, Alina Hartmann, Natascha Osswald, Wolfgang Melchinger, Stefanie Chapman, James A. Hutchinson, Sebastian Haferkamp, Leopold Torster, Julian Kött, Christoffer Gebhardt, Robert Zeiser
{"title":"Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity","authors":"Lukas M. Braun, Sophie Giesler, Geoffroy Andrieux, Roxane Riemer, Nana Talvard-Balland, Sandra Duquesne, Tamina Rückert, Susanne Unger, Stefanie Kreutmair, Melissa Zwick, Marie Follo, Alina Hartmann, Natascha Osswald, Wolfgang Melchinger, Stefanie Chapman, James A. Hutchinson, Sebastian Haferkamp, Leopold Torster, Julian Kött, Christoffer Gebhardt, Robert Zeiser","doi":"10.1016/j.ccell.2025.01.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.004","url":null,"abstract":"Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) with 14 patients reveals low ECP-related toxicity. Overall response rate for all irAEs is 92% (95% confidence interval [CI]: 63.97%–99.81%); colitis-specific complete remission rate is 100% (95% CI: 63.06%–100%). Glucocorticosteroid dosages could be reduced for all patients after ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory T cell activation and CD4<sup>+</sup>IFN-γ<sup>+</sup> T cells in patients with ICI-induced colitis without evidence of loss of anti-tumor immunity. In conclusion, we identify adiponectin as an immunomodulatory molecule that controls ICI-induced irAEs without blocking anti-tumor immunity.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"50 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375424","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}
Cancer CellPub Date : 2025-02-10DOI: 10.1016/j.ccell.2025.01.006
Giampaolo Bianchini, Giulia Viale, Matteo Dugo
{"title":"From intrinsic to adaptive clusters in breast cancer","authors":"Giampaolo Bianchini, Giulia Viale, Matteo Dugo","doi":"10.1016/j.ccell.2025.01.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.006","url":null,"abstract":"The heterogeneity of breast cancers and the availability of several therapeutic options requires prognostic and predictive tools for tailoring adjuvant treatments. In this issue of <em>Cancer Cell</em>, Denkert et al. analyze longitudinal gene-expression data from the Penelope-B trial and identify five adaptive clusters with independent prognostic value to established signatures.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"55 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375420","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}
Cancer CellPub Date : 2025-02-10DOI: 10.1016/j.ccell.2025.01.002
Carsten Denkert, Sivaramakrishna Rachakonda, Thomas Karn, Karsten Weber, Miguel Martin, Frederik Marmé, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Sabine Seiler, Harry D. Bear, Agnieszka K. Witkiewicz, Seock-Ah Im, Angela DeMichele, Anika Pehl, Laura van't Veer, Nicole McCarthy, Thorsten Stiewe, Paul Jank, Karen A. Gelmon, Sibylle Loibl
{"title":"Dynamics of molecular heterogeneity in high-risk luminal breast cancer—From intrinsic to adaptive subtyping","authors":"Carsten Denkert, Sivaramakrishna Rachakonda, Thomas Karn, Karsten Weber, Miguel Martin, Frederik Marmé, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Sabine Seiler, Harry D. Bear, Agnieszka K. Witkiewicz, Seock-Ah Im, Angela DeMichele, Anika Pehl, Laura van't Veer, Nicole McCarthy, Thorsten Stiewe, Paul Jank, Karen A. Gelmon, Sibylle Loibl","doi":"10.1016/j.ccell.2025.01.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.002","url":null,"abstract":"We evaluate therapy-induced molecular heterogeneity in longitudinal samples from high-risk, hormone-receptor positive/HER2-negative breast cancer patients with residual tumor after neoadjuvant chemotherapy from the Penelope-B trial (NCT01864746; EudraCT 2013-001040-62). Intrinsic subtypes are prognostic in pre-therapeutic (Tx) samples (<em>n</em> = 629, <em>p</em> < 0.0001) and post-Tx residual tumors (<em>n</em> = 782, <em>p</em> < 0.0001). After neoadjuvant chemotherapy, a shift of intrinsic subtypes is observed from pre-Tx luminal (Lum) B to post-Tx LumA, with reverse transition back to LumB in metastases. In a combined analysis of 540 paired pre-Tx and post-Tx samples, we identify five adaptive clusters (AC-1–5) based on transcriptomic changes before and after neoadjuvant chemotherapy. These AC-subtypes are prognostic beyond classical intrinsic subtyping, categorizing patients into groups with excellent prognosis (AC-1 and AC-2), poor prognosis (AC-3 and AC-4), and very poor prognosis (AC-5, enriched for basal-like subtype). Our analysis provides a basis for an extended molecular classification of breast cancer patients and improved identification of high-risk patient populations.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"62 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375423","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}
Cancer CellPub Date : 2025-02-10DOI: 10.1016/j.ccell.2025.01.003
Brian S. Henick, Alison M. Taylor, Hiroshi Nakagawa, Kwok-Kin Wong, J. Alan Diehl, Anil K. Rustgi
{"title":"Squamous cell cancers of the aero-upper digestive tract: A unified perspective on biology, genetics, and therapy","authors":"Brian S. Henick, Alison M. Taylor, Hiroshi Nakagawa, Kwok-Kin Wong, J. Alan Diehl, Anil K. Rustgi","doi":"10.1016/j.ccell.2025.01.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.003","url":null,"abstract":"Squamous cell cancers (SCCs) of the head and neck, esophagus, and lung, referred to as aero-upper digestive SCCs, are prevalent in the United States and worldwide. Their incidence and mortality are projected to increase at alarming rates, posing diagnostic, prognostic, and therapeutic challenges. These SCCs share certain epigenetic, genomic, and genetic alterations, immunologic properties, environmental exposures, as well as lifestyle and nutritional risk factors, which may underscore common complex gene-environmental interactions across them. This review focuses upon the frequent shared epigenetic, genomic, and genetic alterations, emerging preclinical model systems, and how this collective knowledge can be leveraged into perspectives on standard of care therapies and mechanisms of resistance, nominating new potential directions in translational therapeutics.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"59 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375422","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}
{"title":"Distinct cellular mechanisms underlie chemotherapies and PD-L1 blockade combinations in triple-negative breast cancer","authors":"Yuanyuan Zhang, Hongyan Chen, Hongnan Mo, Ning Zhao, Xiaoying Sun, Baolin Liu, Ranran Gao, Binghe Xu, Zemin Zhang, Zhihua Liu, Fei Ma","doi":"10.1016/j.ccell.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.007","url":null,"abstract":"Combining immune checkpoint blockade (ICB) with chemotherapy shows promise for treating triple-negative breast cancer (TNBC), though the mechanisms remain incompletely understood. Here, we integrate published and new single-cell RNA sequencing (scRNA-seq) data to investigate the tumor immune microenvironment (TIME) in TNBC patients treated with paclitaxel (PTX), nab-paclitaxel (Nab-PTX), and their combinations with the anti-PD-L1 antibody atezolizumab (ATZ). Compared to ATZ plus PTX, ATZ plus Nab-PTX rewires <em>TCF7</em><sup>+</sup> stem-like effector memory CD8<sup>+</sup> T cells (Tsem) and CD4<sup>+</sup> T follicular helper (Tfh) cells. Nab-paclitaxel, unlike PTX, also reshapes the myeloid compartment, expanding mast cells and pro-inflammatory macrophages. Our analyses in human TNBC and murine models underscore the crucial role of mast cells in orchestrating anti-tumor immune responses, likely by promoting the recruitment and activation of T and B cells. <em>In vivo</em> experiments demonstrate that activating mast cells alongside PD-L1 blockade attenuates TNBC progression, suggesting mast cells as a promising adjunct for enhancing ICB therapy efficacy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"12 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192632","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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