Cancer research最新文献

{"title":"Single Cell Analyses Reveal a Functionally Heterogeneous Exhausted CD8+ T Cell Subpopulation that is Correlated with Response to Checkpoint Therapy in Melanoma","authors":"Kelly M. Mahuron, Osmaan Shahid, Prachi Sao, Clinton Wu, Alexandra M. Haugh, Laura A. Huppert, Lauren S. Levine, Margaret M. Lowe, Michael Alvarado, Markee Micu, Katy K. Tsai, Melissa Chow, Meromit Singer, Jason M. Schenkel, Arlene H. Sharpe, Michael D. Rosenblum, Kristen E. Pauken, Adil I. Daud","doi":"10.1158/0008-5472.can-23-3918","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-3918","url":null,"abstract":"PD-1 pathway inhibitors have revolutionized cancer therapy. However, most patients do not durably benefit, highlighting the need for biomarkers to stratify patients as responders or non-responders. While CD8+ tumor infiltrating lymphocytes (TILs) have been associated with immune checkpoint therapy response, there is not a consensus on which CD8+ TIL subpopulations have the most prognostic value. Preclinical studies have focused on progenitor-like exhausted CD8+ T cells (TPEX), since TPEX proliferate more in response to PD-1 inhibitors than other exhausted T cell (TEX) subpopulations. However, immune checkpoint inhibitor (ICI) treatment drives TPEX differentiation into other TEX populations that can mediate anti-tumor immunity. These data complicate the ability to identify prognostically important T cell populations in patients that predict ICI treatment response. In this study, we found that advanced melanoma patients with ≥20% of CD8+ TILs co-expressing PD-1 and CTLA-4 (termed CPHi TILs) had better objective response rates and survival following PD-1 monotherapy than those below this threshold. Characterization of the CPHi TIL subset using bulk and single cell RNA sequencing showed that while TPEX-like cells were present within the CPHi subset, they were in the minority of these cells. Rather, the CPHi population was numerically dominated by other subsets, including cycling, terminally exhausted, cytotoxic-like, and/or resident memory-like TEX populations, and a subset enriched for glycolytic genes. Collectively, these data show that CPHi TILs correlate with response in melanoma, but this TIL subset is a heterogenous mix of different subpopulations that may differentially contribute to anti-tumor immunity following checkpoint blockade.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"10 2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560602","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":"Macrophage-Derived Itaconate Suppresses Dendritic Cell Function to Promote Acquired Resistance to Anti-PD-1 Immunotherapy","authors":"Xiao Yang, Yue Deng, Ying Ye, Jingshu Meng, Mengyao Su, Wenwen Wei, You Qin, Haibo Zhang, Yu Tian, Suke Deng, Zhiyun Liao, Zhiyuan Zhou, Jie Li, Yan Hu, Bin Zhang, Yajie Sun, Lu Wen, Zhanjie Zhang, Fang Huang, Chao Wan, Kunyu Yang","doi":"10.1158/0008-5472.can-24-2982","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2982","url":null,"abstract":"Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. Here, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti-PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell-derived interferon (IFN)-γ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK-STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the anti-tumor efficacy of anti-PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate (4-OI), suppressed the tumor antigen presentation and cross-priming ability of dendritic cells (DCs), resulting in the impairment of antigen-specific T-cell anti-tumor responses. In summary, these findings identify an IFN-γ-dependent immunometabolic mechanism of anti-PD-1 resistance, providing a promising strategy for combination therapy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"16 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546148","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":"CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance","authors":"Meixi Wang, Fangdi Zou, Shengxin Wang, Yichen Yang, Cong Xia, Lu Chen, Ben Liu, Lian Li, Mulin Jun Li, Haixin Li, Weijie Song, Ruifang Niu, Zhiyong Yuan, Jie Yang, Xiangchun Li, Kexin Chen, Zhiqiang Wu, Zeyun Mi","doi":"10.1158/0008-5472.can-24-3196","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3196","url":null,"abstract":"As the third most common cause of cancer-related mortality, hepatocellular carcinoma (HCC) is a global health concern. Despite its prevalence, treatment options are limited, underscoring the need to identify potential therapeutic targets and strategies. Here, we identified amplification of CRTC2, situated in the 1q21.3 region, due to copy number alterations in HCC. In a cohort of patients with HCC, CRTC2 protein levels were frequently elevated and correlated with poor prognosis. Genetic deletion of CRTC2 significantly impeded the onset and progression of HCC in mouse models. CRTC2 formed cytoplasmic condensates that recruited the m6A reader YTHDF2. Furthermore, CRTC2 promoted the translocation of m6A-modified mRNAs from decay sites to polyribosomes by interacting with PABP1. The activities of CRTC2 counteracted YTHDF2-mediated mRNA degradation to enhance the translational efficiency of specific mRNAs, including those encoding LRP5 and c-Jun. Targeting CRTC2 in hepatocytes using AAV8.sgCRTC2 elicited substantial therapeutic benefits in HCC mouse model and significantly enhanced the sensitivity to lenvatinib. Together, this research elucidates the pivotal role and underlying molecular mechanisms of CRTC2 in hepatocarcinogenesis and lenvatinib-resistance, highlighting its potential clinical and therapeutic applications.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"32 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546205","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":"A Critical Appraisal of the Utility of Targeting Therapy-induced Senescence for Cancer Treatment","authors":"Tareq Saleh, Edward F. Greenberg, Anthony C. Faber, Hisashi Harada, David A. Gewirtz","doi":"10.1158/0008-5472.can-24-2219","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2219","url":null,"abstract":"Cancer chemotherapy and radiotherapy are rarely successful in eliminating the entire tumor population, often leaving behind a subpopulation of senescent cells that can contribute to disease recurrence. These senescent tumor cells also secrete various chemokines and cytokines that may be tumor-promoting and immunosuppressive. Recognition of the deleterious impact of therapy-induced senescence has led to the preclinical development of senolytic compounds that eliminate senescent cells, representing a potential strategy to enhance the efficacy of conventional and targeted anticancer therapy. However, it remains uncertain whether this strategy can or will be translated to the clinic. This review provides a summary of the recent preclinical literature supporting the use of senolytics as an adjunct for cancer treatment, discusses the limitations associated with current preclinical models, and provides perspectives on the clinical development of senolytics in cancer treatment regimens. Overall, preclinical studies support the potential of senolytics to enhance efficacy and prolong the antitumor activity of current standard-of-care cancer therapies that promote senescence. However, further work is needed to develop optimal senolytic agents with the appropriate combination of properties for clinical testing, specifically activity in the context of therapy-induced senescence with acceptable tolerability.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"70 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546149","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":"Editor's Note: PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR.","authors":"Martin L Sos, Mirjam Koker, Barbara A Weir, Stefanie Heynck, Rosalia Rabinovsky, Thomas Zander, Jens M Seeger, Jonathan Weiss, Florian Fischer, Peter Frommolt, Kathrin Michel, Martin Peifer, Craig Mermel, Luc Girard, Michael Peyton, Adi F Gazdar, John D Minna, Levi A Garraway, Hamid Kashkar, William Pao, Matthew Meyerson, Roman K Thomas","doi":"10.1158/0008-5472.CAN-24-5044","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-5044","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 5","pages":"1003"},"PeriodicalIF":12.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536709","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":"Engineered SH3-Derived Sherpabodies Function as a Modular Platform for Targeted T Cell Immunotherapy","authors":"Rogelio A. Hernández-López, Tapio Kesti, Anna R. Mäkelä, Zhe Zhao, Wei Yu, Yurie Tonai, Hector J. Monzo, Kerttu Kalander, Sirpa Leppä, Päivi M. Ojala, Wendell A. Lim, Kalle Saksela","doi":"10.1158/0008-5472.can-24-1959","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1959","url":null,"abstract":"Engineered T cell therapies have emerged as a promising approach for cancer treatment, yet their application to solid tumors remains challenging due to the limited specificity and persistence of current antigen recognition strategies. Here, we introduced sherpabodies, engineered from a human SH3 domain scaffold, as a class of antibody-mimetic proteins capable of precise tumor-associated antigen recognition. A phage display library identified sherpabodies against a panel of popular tumor-associated antigens (TAA), which were subsequently incorporated into second-generation chimeric antigen receptor constructs that were termed sherpabody-guided CARs (SbCARs). These SbCARs demonstrated potent in vitro specificity and cytotoxicity against solid cancer TAAs, without cross-reactivity to closely related proteins. The modularity, versatility, and small size of sherpabodies enabled generation of multipecific SbCARs, in particular TriSbCARs with OR-logic that could robustly activate with cells expressing any or combinations of three cognate TAA targets, as well as circuits with IF-THEN logic in combination with synthetic Notch. In vivo, SbCAR T cells elicited a dose-dependent antitumor response in xenograft mouse models, highlighting their potential for therapeutic application. Furthermore, an inducible SbCAR system displayed enhanced persistence and antitumor activity when compared to constitutive CARs. These findings suggest that sherpabodies represent a versatile and promising platform for the next generation of CAR-T cell therapies, particularly for solid tumors.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"28 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538509","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":"De Novo Serine Synthesis is a Metabolic Vulnerability that can be Exploited to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma","authors":"Manon Teisseire, Umakant Sahu, Julien Parola, Meng-Chen Tsai, Valérie Vial, Jérôme Durivault, Renaud Grépin, Yann Cormerais, Clément Molina, Arthur Gouraud, Gilles Pagès, Issam Ben-Sahra, Sandy Giuliano","doi":"10.1158/0008-5472.can-24-1393","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1393","url":null,"abstract":"Sunitinib is an oral tyrosine kinase inhibitor used in treating advanced renal cell carcinoma (RCC) that exhibits significant efficacy but faces resistance in 30% of patients. Identifying the molecular mechanisms underlying resistance could enable the development of strategies to enhance sunitinib sensitivity. Here, we showed that sunitinib induces a metabolic shift leading to increased serine synthesis in RCC cells. Activation of the GCN2-ATF4 stress response pathway was identified as the mechanistic link between sunitinib treatment and elevated serine production. The increased serine biosynthesis supported nucleotide synthesis and sustained cell proliferation, migration, and invasion following sunitinib treatment. Inhibiting key enzymes in the serine synthesis pathway, such as PHGDH and PSAT1, enhanced the sensitivity of resistant cells to sunitinib. Beyond RCC, similar activation of serine synthesis following sunitinib treatment occurred in a variety of other cancer types, suggesting a shared adaptive response to sunitinib therapy. Together, this study identifies the de novo serine synthesis pathway as a potential target to overcome sunitinib resistance, offering insights into therapeutic strategies applicable across diverse cancer contexts.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"38 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538606","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":"Unlocking the Role of Senescent Cell-Derived Extracellular Vesicles in Immune-Mediated Tumor Suppression.","authors":"Sofia Almeida, Sonia A Melo","doi":"10.1158/0008-5472.CAN-24-4775","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-4775","url":null,"abstract":"<p><p>Senescence, a state of stable cell-cycle arrest, plays a dual role in cancer by suppressing tumor growth while potentially promoting relapse through its secretome, including senescence-associated secretory phenotype factors and senescent cell-derived extracellular vesicles (senEV). In this issue of Cancer Research, Ziglari and colleagues elucidate the role of senEVs in immune-mediated tumor suppression using an in vivo model that preserves immune integrity. Their findings demonstrate that senEVs are distinct from extracellular vesicles of proliferating cells, enriched with molecules that recruit and activate antigen-presenting cells and orchestrate TH17-driven antitumor immunity. Notably, the absence of senEVs accelerated tumor relapse, highlighting their necessity in senescence surveillance. Despite these advancements, further work is required to identify the specific senEV cargo driving antigen-presenting cell activation and to define the long-term dynamics of tumor relapse. This study underscores the potential of senEVs as biomarkers and therapeutic targets to enhance immune clearance of senescent cells and prevent cancer recurrence. The findings in this study pave the way for innovative strategies to modulate senescence and its secretome in cancer therapy. See related article by Ziglari et al., p. 859.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 5","pages":"833-835"},"PeriodicalIF":12.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536433","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":"CXCL10 Secreted by Pericytes Mediates TNFα-Induced Vascular Leakage in Tumors and Enhances Extravasation of Nanoparticle-Based Chemotherapeutics.","authors":"Ann L.B. Seynhaeve, Hui Liu, Marjolein I. Priester, Mike Valentijn, Conny van Holten-Neelen, Rutger W.W. Brouwer, Mandy van Brakel, Willem A. Dik, Wilfred F.J. van IJcken, Reno Debets, Andrew P. Stubbs, Timo L. M. ten Hagen","doi":"10.1158/0008-5472.can-24-3833","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3833","url":null,"abstract":"Tumor necrosis factor-alpha (TNFα) induces vascular permeability and plays an important role in inflammation. In addition, TNFα-induced vascular leakage is involved in the increased extravasation of nanoparticle-formulated chemotherapeutic drugs, improving drug delivery and subsequent tumor response. Here, we uncovered a positive correlation between the presence of pericytes in the tumor-associated vasculature and TNFα-induced leakage and drug delivery, especially when drugs were encapsulated in nanoparticles. RNA-sequencing and pathway analysis identified high expression of CXCL10 in TNFα-stimulated pericytes. In addition, TNFα increased CXCL10 protein production by pericytes in vitro. In animal studies, tumor types with vessels with high pericyte coverage showed enhanced permeability and extravasation of drugs encapsulated in nanoparticles following treatment with TNFα, which could be blocked with a CXCL10 neutralizing antibody. In contrast, tumors harboring vessels with low pericyte numbers did not display increased drug extravasation in response to TNFα. Lack of pericyte coverage could be compensated by co-administration of CXCL10. These findings reveal a mechanism by which TNFα induces CXCL10 release from pericytes, resulting in increased endothelial permeability, vascular leakage, and drug delivery.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"101 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506897","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":"Tumorigenesis Driven by BRAFV600E Requires Secondary Mutations that Overcome it's Feedback Inhibition of RAC1 and Migration.","authors":"Sunyana Gadal, Jacob A Boyer, Simon F Roy, Noah A Outmezguine, Malvika Sharma, Hongyan Li, Ning Fan, Eric Chan, Yevgeniy Romin, Afsar Barlas, Qing Chang, Priya Pancholi, Neilawattie Merna Timaul, Michael Overholtzer, Rona Yaeger, Katia Manova-Todorova, Elisa de Stanchina, Marcus W Bosenberg, Neal Rosen","doi":"10.1158/0008-5472.CAN-24-2220","DOIUrl":"10.1158/0008-5472.CAN-24-2220","url":null,"abstract":"<p><p>BRAFV600E mutations occur in 46% of melanomas and drive high levels of ERK activity and ERK-dependent proliferation. However, BRAFV600E is insufficient to drive melanoma in genetically engineered mouse models, and 82% of human benign nevi harbor BRAFV600E mutations. We found that BRAFV600E inhibited mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition induced RAC1 activation and restored migration and invasion. In cells with BRAFV600E, mutant RAC1 or PTEN inactivation restored RAC1 activity and cell motility. Together, these lesions occurred in 26% of melanomas with BRAFV600E mutations. Thus, although BRAFV600E activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of RAC1. Secondary mutations are, therefore, required for tumorigenesis. One mechanism underlying tumor evolution may be the selection of lesions that rescue the deleterious effects of oncogenic drivers.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482354","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}