Cancer immunology research最新文献

{"title":"Tumor Cell-Intrinsic Decr2 Regulates Ferroptosis and Immunotherapy Efficacy.","authors":"Shuyin Li, Jason W Shapiro, Hardik Shah, Emily F Higgs, Lishi Xie, Yaopeng Li, Yuanyuan Zha, Jonathan Trujillo, Alexandra Cabanov, Tyler A Jones, Blake Flood, Ken Hatogai, Ruxandra Tonea, Justin Kline, Thomas F Gajewski","doi":"10.1158/2326-6066.CIR-24-0519","DOIUrl":"10.1158/2326-6066.CIR-24-0519","url":null,"abstract":"<p><p>Immune checkpoint blockade therapies have transformed the landscape of cancer care, but durable clinical responses are achieved in only a subset of patients. To identify genes that can contribute to immunotherapy resistance, a genome-wide CRISPR screen was performed. Selection for mutants that are resistant to T cell-mediated killing identified the gene encoding Decr2, a peroxisomal 2,4-dienoyl-CoA reductase. We show that Decr2 in tumor cells participates in CD8+ T cell-mediated tumor cell killing and that Decr2 knockdown reduces the efficacy of anti-PD-L1 therapy in vivo. Knocking down Decr2 expression resulted in diminished ferroptosis that was associated with reduced induction of polyunsaturated ether phospholipids. Analysis of tumor RNA sequencing data from patients with melanoma revealed that upregulation of Decr2 was associated with anti-PD-1 efficacy, and patients with Decr2 gene deletions showed worse clinical outcomes. Our results identify Decr2 as a regulator of immunomediated tumor cell killing, with implications for improving immunotherapy efficacy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1284-1302"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Myeloid Trem2 Reprograms the Immunosuppressive Niche and Potentiates Checkpoint Immunotherapy in NASH-Driven Hepatocarcinogenesis.","authors":"Ziyi Wang, Yu Zhang, Xiangdong Li, Nan Xia, Sheng Han, Liyong Pu, Xuehao Wang","doi":"10.1158/2326-6066.CIR-24-1088","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1088","url":null,"abstract":"<p><p>Macrophages expressing Trem2 play a pivotal role in promoting non-alcoholic steatohepatitis (NASH; also known as metabolic dysfunction-associated steatohepatitis, MASH) progression to hepatocellular carcinoma (HCC). Despite the widespread clinical use of anti-PD1 immune checkpoint blockade, its therapeutic efficacy in NASH-driven HCC remains suboptimal. This study investigates the mechanisms by which NAM Trem2 influences the response of NASH-driven HCC to immunotherapy. Clinical analysis revealed that elevated Trem2 expression in NASH is positively correlated with accumulation of neutrophil extracellular traps (NET) and infiltration of PD1+Eomes+CD8+ T cells and regulatory T cells (Tregs). Myeloid-specific knockout of Trem2 (Trem2Δmye) led to impaired macrophage reprogramming, resulting in the accumulation of pro-inflammatory Ly6ChiCX3CR1lo macrophages, which enhanced degradation of NETs in NASH. Trem2Δmye also disrupted TGF-β production via P-Syk-dependent efferocytosis, collectively suppressing the differentiation of PD1+Eomes+CD8+ T cells and Tregs. The efficacy of anti-PD1 therapy in inhibiting NASH-driven HCC progression was also significantly enhanced by Trem2Δmye, primarily through the downregulation of Treg CXCR4 expression mediated by increased NET degradation. These therapeutic effects were further amplified when combined with the CXCR2 inhibitor AZD5069. Our findings identify Trem2 as a central regulator of the NASH-driven HCC immunosuppressive niche, and suggest a combinatorial therapeutic strategy that targets both myeloid reprogramming and NETosis to overcome immunotherapy resistance in metabolic liver cancer progression.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764627","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":"CTG-Initiated Cryptic Peptide Translation Up- and Downstream of a Canonical ATG Start Codon Is Enhanced by TLR Stimulation and Induces Tumor Regression in Mice.","authors":"Ziye Song, Youkyung Lim, Anneloes van Krimpen, Mitchell A A Geleijnse, Manon Messchendorp, Jane S A Voerman, Ling Li, Emma G M Tondeur, Gunja Mishra, Brett J Hos, Dwin G B Grashof, Ralph Stadhouders, Harmen J G van de Werken, Peter D Katsikis, Christopher Schliehe","doi":"10.1158/2326-6066.CIR-24-0467","DOIUrl":"10.1158/2326-6066.CIR-24-0467","url":null,"abstract":"<p><p>Cytotoxic T lymphocytes screen cells for signs of infection and transformation by recognizing peptides displayed on MHC class I molecules. Next to canonical ATG-initiated open reading frames (ORF), noncanonical translation can result in synthesis of nonconventional or \"cryptic\" polypeptides. These can originate from translation initiation at noncanonical start codons, a process previously associated with inflammation and oncogenic transformation. Cryptic translation products are efficiently presented on MHC class I molecules and therefore increasingly recognized as potential targets for cancer immunotherapy. In this study, we studied the impact of localization of a CTG-initiated ORF relative to a canonical ATG start codon on cryptic expression after innate immune stimulation. We generated immortalized C57BL/6J mouse-derived bone marrow progenitor cells (HoxB8) expressing tandem minigene constructs, which encoded a CTG-driven chicken ovalbumin-derived SIINFEKL (S8L) epitope (CTG-S8L; H-2Kb restriced) either up- or downstream of a canonical ATG-initiated UTY-derived peptide WI9. The treatment of HoxB8-derived macrophages with Toll-like receptor agonists enhanced position-independent CTG-S8L translation, without affecting ATG-driven expression. Downstream CTG-S8L translation was driven by leaky scanning or ribosome re-initiation rather than read-through translation. Mouse AE17 mesothelioma and B16F10 melanoma cells expressing cryptic S8L either up- or downstream of a canonical ORF were efficiently killed by H-2Kb/S8L-restriced OT-I T cells in vitro, even though their antigen expression levels were extremely low. Mice implanted with tumors expressing cryptic S8L showed delayed tumor progression in vivo. In summary, our study contributes to the characterization of noncanonical start codon-driven cryptic antigen translation and highlights its potential for cancer immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1246-1265"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secretion of a VEGF-Blocking scFv Enhances CAR T-cell Potency.","authors":"Valentina M Supper, Hannah Donner, Filippo Birocchi, Alexandra Bratt, Giulia Escobar, Michael C Kann, Sangwoo Park, Grace Martin, Felix Korell, Hana Takei, Alexander Armstrong, Aiyana Parker, Diego Salas-Benito, Eli P Darnell, Stefanie R Bailey, Tamina Kienka, Merle Philips, Amanda Bouffard, Sadie Goncalves, Bryan D Choi, Nicholas J Haradhvala, Marcela V Maus, Mark B Leick","doi":"10.1158/2326-6066.CIR-24-0876","DOIUrl":"10.1158/2326-6066.CIR-24-0876","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy is an effective treatment strategy for B-cell malignancies; however, its efficacy in solid tumors remains limited. VEGF-targeted drugs are used as antitumor agents to target abnormal tumor vasculature; however, toxicities associated with systemic VEGF blockade limit their maximal therapeutic benefit. Increasing evidence suggests a role for VEGF in the immunosuppressive tumor microenvironment, including through direct induction of T cell-effector dysfunction. In this study, we show that CAR T cells from patients treated with FDA-approved CAR T-cell products express members of the VEGF signaling pathway, and this expression is correlated with patient nonresponse. To overcome putative VEGF-induced CAR T-cell dysfunction and deliver local VEGF blockade, we generated CAR T cells that secrete a VEGF-targeting single-chain variable fragment to block T-cell and tumor-derived VEGF within the tumor microenvironment. These CAR T cells potently inhibited VEGF signaling and angiogenesis in vitro and exhibited enhanced activation, cytotoxicity, proliferation, and effector function across different antigen and solid tumor contexts. VEGF single-chain variable fragment-secreting CAR T cells showed improved tumor control in immunocompromised murine metastatic and orthotopic models of ovarian and lung cancer. These findings suggest that CAR T cell-secreted VEGF blockade augments CAR T-cell performance, inhibits VEGF without systemic toxicity, and warrants further development.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1132-1144"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198264","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":"Neutrophil Extracellular Traps Modulate Recruitment and Immunosuppression of Macrophages in Pancreatic Adenocarcinoma.","authors":"Hillary G Pratt, Alyson M Stevens, Michael Sestito, Mercy Ojetunde, Abby D Ivey, Nicole E Mihalik, Kayla J Steinberger, Britney Niemann, E Hannah Hoblitzell, Edwin Wan, Timothy D Eubank, Brian A Boone","doi":"10.1158/2326-6066.CIR-24-0534","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0534","url":null,"abstract":"<p><p>Pancreatic adenocarcinoma (PDAC) has a dismal survival rate due to limited effective therapies. While studies have focused on innate immune cell influence on adaptive immune cell functions, few have explored interactions between innate immune cells, which modulate the unique PDAC tumor microenvironment (TME). Macrophages are responsible for clearance of neutrophil-mediated inflammation in physiologic immune responses; however, these cells co-exist in PDAC. We sought to determine how neutrophil extracellular traps (NETs), neutrophil release of decondensed chromatin and intracellular contents, affect monocyte/macrophage populations in the PDAC TME. Utilizing samples from patients with PDAC, we demonstrate elevated monocyte chemokine CCL2 in plasma and elevated NET CitH3 and pan-macrophage marker CD68 in the PDAC TME via fluorescent immunohistochemistry. To determine how NETs impacted macrophage populations in the PDAC TME, we depleted NETs with DNase I and with genetic knockout of the PAD4 enzyme and found an elevation in pan-macrophage marker F4/80. The depletion led to increased T cell stimulatory signal CD80 while the pro-tumor macrophage marker CD206 was decreased. We further demonstrate that macrophages in the NET-deficient PDAC TME may be recruited through the CCL2/CCR2 axis, in which CCL2 can be released from tumor cells and macrophages in the presence of IFN-. Taken together, our findings reveal that inhibition of NETs can prime the innate immune response toward an anti-tumor phenotype.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752499","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":"PI3K/Akt signaling pathway regulates CD155 expression involved in resistance to cancer immunotherapy.","authors":"Katsushige Kawase, Shusuke Kawashima, Tatsuya Nishi, Takashi Inozume, Takao Morinaga, Masahito Kawazu, Toyoyuki Hanazawa, Yosuke Togashi","doi":"10.1158/2326-6066.CIR-24-0853","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0853","url":null,"abstract":"<p><p>Despite the effectiveness of anti-programmed death 1 (PD-1)/PD-1 ligand 1 monoclonal antibodies against various cancers, resistance remains a significant issue among patients. The immunosuppressive T cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD155 axis has emerged as a key mechanism contributing to this resistance. However, the intricacies of CD155 expression are not fully elucidated. In this study, we aimed to identify the key molecules involved in the regulation of CD155 expression and explore their role in modulating CD155 within the tumor microenvironment (TME). By employing clustered regularly interspaced palindromic repeats (CRISPR) screening, we identified dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) as one of the key regulators of CD155 expression. Subsequent inhibition of Dyrk1a through CRISPR/CRISPR-associated protein 9 (Cas9) technology or treatment with DYRK1A inhibitors effectively mitigated PD-1 blockade resistance. Moreover, in certain head and neck squamous cell carcinoma (HNSCC) cell lines, cetuximab-mediated epidermal growth factor receptor blockade reduced CD155 expression by targeting downstream PI3K/Akt signaling. In patients with HNSCC (n = 96), CD155 expression correlated with Akt phosphorylation, particularly impacting PD-1 blockade resistance in those with high CD8+ T cell infiltration. These findings underscore the role of the PI3K/Akt signaling pathway in regulating CD155 expression, which may influence resistance to PD-1 blockade therapies in a variety of cancers, particularly those characterized by an inflamed TME. This study suggests that targeting the PI3K/Akt pathway could overcome resistance, particularly in cancers with an inflamed TME and high CD155 expression.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752500","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":"TIGIT affects CAR NK cell effector function in the solid tumor microenvironment by modulating immune synapse strength.","authors":"Ishwar Navin, Matthew Dysthe, Prashant S Menon, Corrine Baumgartner, Tim Sauer, Navin Varadarajan, Robin Parihar","doi":"10.1158/2326-6066.CIR-24-0919","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0919","url":null,"abstract":"<p><p>Therapies using natural killer (NK) cells that express chimeric antigen receptors (CAR-NKs) have been successfully employed against hematological malignancies. However, solid tumors resist CAR NKs partly by enriching tumor microenvironments with ligands for NK cell inhibitory receptors. Although the NK inhibitory receptor TIGIT has been implicated in impaired anti tumor activity of endogenous NK cells, the consequences of TIGIT expression on engineered CAR NKs has not been explored. To address this gap, we compared TIGIT-expressing and TIGIT deleted human CAR-NKs targeting the GD2 solid tumor antigen in tumor immune microenvironment (TiME) co-cultures and in vivo TiME xenografts designed to mimic the immunosuppressive environment of solid tumors. TIGIT deleted GD2.CAR-NKs exhibited antitumor activity, expanded, and persisted within TIGIT ligand enriched solid tumor environments while TIGIT expressing CAR-NKs did not. Mechanistic experiments revealed that the improved tumor control resulting from TIGIT loss on CAR-NKs was not dependent on DNAM-1 activation or enhanced cytotoxic potential, but rather on downregulation of cell adhesion molecules, weakened cell avidity, and reduced synapse contact duration that, in concert, improved serial killing and allowed more efficient tumor destruction. Our study highlights a novel non canonical role for TIGIT in modulating CAR-NK activity that may guide strategies to overcome inhibitory NK receptors like TIGIT and improve efficacy of CAR NKs against solid tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741284","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":"SPP1+ Tumor-associated Macrophages Drive Immunotherapy Resistance via CD8+ T-Cell Dysfunction in Clear Cell Renal Cell Carcinoma.","authors":"Wenbin Jiang, Li Liu, Ziyang Xu, Youqi Qiu, Boyu Zhang, Jiangting Cheng, Jiyan Luo, Yang Qu, Jianming Guo, Jiejie Xu","doi":"10.1158/2326-6066.CIR-24-1146","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1146","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) are key regulators of tumor immunity. With advances in single-cell analyses, SPP1+ TAMs have been observed across multiple tumor sites. However, their clinical relevance and phenotypic characteristics in clear cell renal cell carcinoma (ccRCC) have not been comprehensively delineated. Using patient-level data from two in-house cohorts (n=355) we explored the relationship between SPP1+ TAM infiltration and therapeutic response as well as prognosis in ccRCC. Four publicly available datasets consisting of 1,741 ccRCC patients were included for external validation. Cytometry by time-of-flight (CyTOF) and flow cytometry were utilized to phenotype SPP1+ TAMs and establish their impact on CD8+ T cells. Further, we established an ex vivo culture system to test the potential therapeutic value of targeting SPP1 alone and in conjunction with PD-1 inhibitors in ccRCC. We found that patients with high SPP1+ TAM infiltration exhibited worse response to immunotherapy and dismal prognosis in ccRCC. SPP1+ TAMs exhibited an immunosuppressive and pro-tumor phenotype, and were related to impaired effector function and terminal differentiation of CD8+ T cells. Blockade of SPP1 mitigated the pro-tumor tumor microenvironment and reinvigorated CD8+ T-cell function. Combining PD-1 blockade with SPP1 blockade boosted the expansion of CD8+ T cells and enhanced antitumor efficacy. Together, these data indicate that elevated infiltration of SPP1+ TAMs is related to worse response to immunotherapy and dysfunction of CD8+ T cells in ccRCC. We conclude that SPP1 may serve as a potential therapeutic target in ccRCC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663871","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":"EML4-ALK rearrangement creates a distinctive myeloid cell-dominant immunosuppressive microenvironment in lung cancer.","authors":"Kosuke Arai, Yukari Nishito, Hideaki Mizuno, Noriko Motoi, Nobuyoshi Hiraoka, Masanori Fuse, Yasuhito Arai, Tatsuhiro Shibata, Yukiko Sonobe, Yoko Kayukawa, Toru Maruyama, Hironori Fukuda, Yukihiro Mizoguchi, Yukiko Aikawa, Yukihiro Yoshida, Shun-Ichi Watanabe, Hiromi Sakamoto, Makiko Yamashita, Shigehisa Kitano, Yuki Nagata, Risa Mitsumori, Kouichi Ozaki, Shumpei Niida, Yae Kanai, Akiyoshi Hirayama, Tomoyoshi Soga, Teruhiko Yoshida, Kazuki Yasuda, Atsushi Ochiai, Hiroyuki Tsunoda, Kazunori Aoki","doi":"10.1158/2326-6066.CIR-24-0532","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0532","url":null,"abstract":"<p><p>Tyrosine kinase inhibitors (TKIs) are initially efficacious against anaplastic lymphoma kinase (ALK) fusion gene-positive lung adenocarcinoma (ALK+ LUAD), but acquired resistance inevitably occurs. Therefore, alternative treatment strategies are needed for TKI-resistant cases. Although the use of immune checkpoint inhibitors (ICIs) has improved the prognosis of patients with lung cancer, patients with ALK+ LUAD exhibit little or no response to immunotherapy and the underlying resistance mechanisms remain unknown. Here, we explored the immunological status of the tumor microenvironment (TME) in ALK+ LUAD tissues. Tumor-infiltrating leukocyte analysis revealed reduced numbers of effector T cells and increased myeloid-derived suppressor cells (MDSCs) relative to ALK- LUAD cases, indicating that ALK+ LUAD has a myeloid cell-dominant immunosuppressive TME. Single-cell RNA-sequencing analysis identified a subset of macrophages that expressed most T cell-attractant chemokines (CXCL9, CXCL10, and CXCL11), and the macrophages were inactivated in ALK+ LUAD. In contrast, ALK+ LUAD expressed high levels of MDSC-attractant chemokines (CXCL1 and CXCL8). In addition, ALK+ LUAD showed higher levels of IL-6, an MDSC-inducing cytokine, than ALK- LUAD. An IL-6R inhibitor transformed the TME in a murine ALK+ LUAD model, shifting it from an immunosuppressive to a T cell-dominant status. Although ICI monotherapy lacked antitumor effects, a combination of ICI and the IL-6R inhibitor had significant antitumor effects in mice. Our findings illustrate the molecular basis of fusion gene-mediated immunosuppressive TMEs, providing a rationale for a novel combination immunotherapy for ALK+ LUAD.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590507","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":"Vγ9Vδ2 T Cells Express an Antitumor Profile Associated with Anti-PD-(L)1 Responses and Activation Defects Restored by Anti-BTN3A in Triple-Negative Breast Cancer.","authors":"Stéphane Fattori, Laurent Gorvel, Marie-Sarah Rouvière, Samuel Granjeaud, Amira Ben Amara, Manon Richaud, Nicolas Boucherit, Carole Tarpin, Jihane Pakradouni, Julien Hédou, Grégoire Bellan, Brice Gaudilliere, Emmanuelle Charafe-Jauffret, Gilles Houvenaeghel, Eric Lambaudie, François Bertucci, Jean-Jacques Fournié, Anthony Gonçalves, Philippe Rochigneux, Anne-Sophie Chrétien, Daniel Olive","doi":"10.1158/2326-6066.CIR-24-1285","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1285","url":null,"abstract":"<p><p>Vγ9Vδ2 (TCRVγ9+ TCRVδ2+) T cells are promising immunotherapeutic targets with effective antitumor properties in both in vitro and preclinical models of triple-negative breast cancer (TNBC). However, no information regarding their potential role in the context of human TNBC progression and response to immunotherapy has been reported. One key reason for this is the scarcity of Vγ9Vδ2 T cell infiltrates relative to their Vδ1 (TCRVδ1+) and αβCD8 (TCRαβ+ CD8αβ+) T cell counterparts. We provide a comprehensive single-cell profiling of Vγ9Vδ2 T cells from patients with TNBC, prior to and following PD-(L)1 blockade therapy. We report that baseline Vγ9Vδ2 T cell infiltrate expressing a unique cytotoxic type-I (Tc1) phenotype could be associated with improved survival in patients with TNBC. Vγ9Vδ2 T cells harboring characteristics of enhanced antitumor activity (KLRC1+) were further associated with improved response to PD-(L)1 blockade therapy in patients with TNBC. Vγ9Vδ2 T cells had low expression levels of T cell exhaustion (PD-1Low TOXLow) and TCR signaling hallmarks compared to Vδ1 and αβCD8 T cells, along with skewed differentiation profiles towards early effector memory phenotypes, both before and after anti-PD-1 therapy in TNBC tumors. Consistently, we observed a limited activity of anti-PD-1 on tumor-infiltrating Vγ9Vδ2 T cells. In vitro, the use of anti-butyrophilin-3A (BTN3A) antibodies in addition to the anti-PD-1 reinvigorated the Tc1 functions of peripheral Vγ9Vδ2 T cells from patients with breast cancer. Together, these data provide a rationale for Vγ9Vδ2 T cell-based combination therapy in patients with TNBC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583085","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}