Cancer immunology research最新文献

{"title":"A PSMA-targeted Tri-specific Killer Engager enhances NK cell cytotoxicity against prostate cancer.","authors":"Shee Kwan Phung, Nicholas A Zorko, Yvette Soignier, Rhett L Waller, Madison Shackelford, Joshua T Walker, Trygve D Nelson, Carly Selleck, Laura E Bendzick, Laura E Kotz, Quinlan M Kile, Asha J Bozicevich, Sarah E Miller, Melissa Khaw, Mihir Shetty, Peter Hinderlie, Michael Ehrhardt, Yingming Li, Xianghua Luo, Scott M Dehm, Emmanuel S Antonarakis, Philippa R Kennedy, Jeffrey S Miller, Martin Felices","doi":"10.1158/2326-6066.CIR-24-0273","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0273","url":null,"abstract":"<p><p>Natural killer (NK) cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with co-activation may enhance NK cell function in mCRPC. We describe a Tri-specific Killer Engager (TriKE) construct that engages with the activating receptor CD16 on NK cells, prostate-specific membrane antigen (PSMA) on mCRPC cells, and has an interleukin (IL)-15 moiety that is essential for NK cell survival, proliferation, and priming. We show that the PSMA TriKE specifically binds to PSMA-expressing cells and significantly enhances expansion, degranulation and cytokine production of NK cells derived from healthy donors or prostate cancer patients. Bystander killing of PSMA-negative was also achieved with PSMA TriKE treatment when co-cultured with PSMA-positive cells, suggesting potential PSMA TriKE benefit in controlling tumor antigen escape. When tested under physiologic conditions recapitulating the mCRPC tumor microenvironment (TME), NK cells treated with PSMA TriKE and prolonged exposure to hypoxia or MDSCs maintained their potent function while IL-15 treated NK cells showed greatly impaired cytotoxicity. Finally, in vivo testing of PSMA TriKE showed improved tumor control and survival of mice as compared to IL-15 and untreated control groups. In conclusion, PSMA TriKE demonstrates potential as a new therapy for advanced prostate cancer by providing additional signals to NK cells to maximize their anti-tumor potential in prostate cancer, especially in the setting of a hostile TME.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638431","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":"Correction: CD28 Costimulatory Domain-Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function.","authors":"Justin C Boucher, Gongbo Li, Hiroshi Kotani, Maria L Cabral, Dylan Morrissey, Sae Bom Lee, Kristen Spitler, Nolan J Beatty, Estelle V Cervantes, Bishwas Shrestha, Bin Yu, Aslamuzzaman Kazi, Xuefeng Wang, Said M Sebti, Marco L Davila","doi":"10.1158/2326-6066.CIR-24-1029","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1029","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"OF1"},"PeriodicalIF":8.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614402","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":"Targeting of tumoral NAC1 mitigates myeloid-derived suppressor cell-mediated immunosuppression and potentiates anti-PD-1 therapy in ovarian cancer.","authors":"Shunli Dong, Cong Ye, Bin Li, Fanglin Lv, Lu Zhang, Shumin Yang, Fang Wang, Mingxian Zhu, Mingxuan Zhou, Fanfan Guo, Zhenyun Li, Lei Peng, Cheng Ji, Xialiang Lu, Yan Cheng, Xingcong Ren, Youguo Chen, Jinhua Zhou, Jinming Yang, Yi Zhang","doi":"10.1158/2326-6066.CIR-24-0084","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0084","url":null,"abstract":"<p><p>Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer with a low rate of response to immunotherapy such as immune checkpoint blockade (ICB) therapy. Here, we report that nucleus accumbens-associated protein 1 (NAC1), a putative driver of EOC, has a critical role in immune evasion. We showed in murine ovarian cancer models that depleting or inhibiting tumoral NAC1 reduced the recruitment and immunosuppressive function of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME), led to significant increases of cytotoxic tumor-infiltrating CD8+ T cells, and promoted antitumor immunity and suppressed tumor progression. We further showed that tumoral NAC1 directly enhanced the transcription of CXCL16, by binding to CXCR6, thereby promoting MDSC recruitment to the tumor. Moreover, lipid C20:1T produced by NAC1-expressing tumor cells fueled oxidative metabolism of MDSCs and promoted their immune-suppressive function. We also showed that NIC3, a small molecule inhibitor of NAC1, was able to sensitize mice-bearing NAC1-expressing ovarian tumors to anti-PD-1 therapy. Our study reveals a critical role for NAC1 in controlling tumor infiltration of MDSCs and in modulating the efficacy of ICB therapy. Thus, targeting of NAC1 may be exploited to sensitize ovarian cancer to immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614540","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":"Inflammatory stress determines the need for chemotherapy in patients with HER2-positive esophagogastric adenocarcinoma receiving targeted and immunotherapy.","authors":"Joseph Tintelnot, Lisa Paschold, Eray Goekkurt, Christoph Schultheiss, Urte Matschl, Mariana Santos Cruz, Marcus Bauer, Claudia Wickenhauser, Peter Thuss-Patience, Sylvie Lorenzen, Thomas J Ettrich, Jorge Riera-Knorrenschild, Lutz Jacobasch, Albrecht Kretzschmar, Stefan Kubicka, Salah-Eddin Al-Batran, Anke Reinacher-Schick, Daniel Pink, Carsten Bokemeyer, Marianne Sinn, Udo Lindig, Axel Hinke, Susanna Hegewisch-Becker, Alexander Stein, Mascha Binder","doi":"10.1158/2326-6066.CIR-24-0561","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0561","url":null,"abstract":"<p><p>Anti-PD-1, trastuzumab, and chemotherapy are used in the treatment of patients with advanced HER2-positive esophagogastric adenocarcinoma (EGA), but long-term survival remains limited. Herein, we report extended follow-up data from the INTEGA trial (NCT03409848), which investigated the efficacy of the anti-PD-1 nivolumab, trastuzumab, and FOLFOX chemotherapy (FOLFOX arm) in comparison to a chemotherapy-free regimen involving nivolumab, trastuzumab, and the anti-CTLA-4 ipilimumab (Ipi arm) in the first-line setting for advanced disease. The 12-month overall survival (OS) showed no statistical difference between the arms, with 57% OS (95% CI: 41%-71%) in the Ipi arm and 70% OS (95% CI: 54%-82%) in the FOLFOX arm. Crossing of the survival curves indicated a potential long-term benefit for some patients within the Ipi arm, but early progressors in the Ipi arm underlined the need for biomarker-guided strategies to optimize treatment selection. To this end, metabolomic and cytokine analysis demonstrated elevated levels of normetanephrine, cortisol, and interleukin 6 (IL-6) in immunotherapy-unresponsive patients in the Ipi arm, suggesting a role for systemic inflammatory stress in modulating antitumor immune responses. Patients with this signature also showed an increased neutrophil-to-lymphocyte ratio (NLR) that persisted in the Ipi arm, but not in the FOLFOX arm, and strongly correlated with survival. Furthermore, a low NLR characterized patients benefiting from immune- and targeted therapy without the need for additional chemotherapy. This data suggests that patient selection based on inflammatory stress-driven immune changes could help to customize first-line treatment in patients with advanced HER2-positive EGA to potentially improve long-term survival.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614424","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":"Combination CXCR4 and PD1 blockade enhances intratumoral dendritic cell activation and immune responses against hepatocellular carcinoma.","authors":"Satoru Morita, Pin-Ji Lei, Kohei Shigeta, Tomofumi Ando, Tatsuya Kobayashi, Hiroto Kikuchi, Aya Matsui, Peigen Huang, Mikael J Pittet, Dan G Duda","doi":"10.1158/2326-6066.CIR-24-0324","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0324","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of unresectable hepatocellular carcinoma (HCC), but their impressive efficacy is seen in just a fraction of patients. One key mechanism of immunotherapy resistance is the paucity of dendritic cells (DCs) in liver malignancies. Here, we tested combination blockade of programmed death receptor 1 (PD1) and CXCR4, a receptor for CXCL12, a pleiotropic factor that mediates immunosuppression in tumors. Using orthotopic grafted and autochthonous HCC models with underlying liver damage, we evaluated treatment feasibility and efficacy. In addition, we examined the effects of treatment using immunofluorescence, flow cytometric analysis of DCs in vivo and in vitro, and RNA-sequencing. Combination anti-CXCR4 and anti-PD1therapy was safe and significantly inhibited tumor growth and prolonged survival in all murine preclinical models of HCC tested. The combination treatment successfully reprogrammed antigen-presenting cells, revealing the potential role of conventional type 1 DCs (cDC1s) in the HCC microenvironment. Moreover, DC reprogramming enhanced anticancer immunity by facilitating CD8+ T-cell accumulation and activation in the HCC tissue. The effectiveness of anti-CXCR4/PD1 therapy was compromised entirely in Batf3-KO mice deficient in cDC1s. Thus, combined CXCR4/PD1 blockade can reprogram intra-tumoral cDC1s and holds the potential to potentiate antitumor immune response against HCC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603039","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":"An Engineered Self-biomineralized Oncolytic Adenovirus Induces Effective Antitumor Immunity and Synergizes With Immune Checkpoint Blockade.","authors":"Shibing Wang, Xue Yang, Ying-Yu Ma, Junjie Wu, Ketao Jin, Ruibo Zhao, Hai Zou, Xiaozhou Mou","doi":"10.1158/2326-6066.CIR-23-0957","DOIUrl":"10.1158/2326-6066.CIR-23-0957","url":null,"abstract":"<p><p>Oncolytic adenoviruses (oADV) are promising cancer treatment agents. However, in vivo hepatic sequestration and the host immunologic response against the agents limit the therapeutic potential of oADVs. In this study, we present a combined method with a rational design for improving oADV infection efficiency, immunogenicity, and treatment efficacy by self-biomineralization. We integrated the biomimetic nucleopeptide W6p into the capsid of oADV using reverse genetics, allowing calcium phosphate mineralization to be biologically induced on the surface of oADV under physiologic conditions, resulting in a mineral exterior. This self-biomineralized, modified oADV (oADV-W6-CaP) enhanced infection efficiency and therapeutic efficacy in coxsackievirus and adenovirus receptor (CAR)-negative cancer cells wherein protecting them against neutralization by preexisting neutralizing antibodies. In subcutaneous mouse tumor models, systemic injection of oADV-W6-CaP demonstrated improved antitumor effectiveness, which was associated with increased T-cell infiltration and CD8+ T-cell activation. In addition, the anticancer immune response elicited by oADV-W6-CaP was dependent on CD8+ T cells, which mediated long-term immunologic memory and systemic antitumor immunity against the same tumor. Finally, the addition of PD1 or CD47 inhibition boosted the anticancer effects of oADV-W6-CaP and increased the rate of complete tumor clearance in tumor-bearing animals. The self-biomineralized oADV shifted the suppressive tumor microenvironment from a \"cold\" to \"hot\" state and synergized with immune checkpoint blockade to exert outstanding tumoricidal effects, demonstrating promising potential for cancer immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1640-1654"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878431","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":"CD36+ Proinflammatory Macrophages Interact with ZCCHC12+ Tumor Cells in Papillary Thyroid Cancer Promoting Tumor Progression and Recurrence.","authors":"Xin Zhang, Limei Guo, Wenyu Tian, Ying Yang, Yue Yin, Yaruo Qiu, Weixuan Wang, Yang Li, Guangze Zhang, Xuyang Zhao, Guangxi Wang, Zhiqiang Lin, Meng Yang, Wei Zhao, Dan Lu","doi":"10.1158/2326-6066.CIR-23-1047","DOIUrl":"10.1158/2326-6066.CIR-23-1047","url":null,"abstract":"<p><p>Local recurrence and distal metastasis negatively impact the survival and quality of life in patients with papillary thyroid cancer (PTC). Therefore, identifying potential biomarkers and therapeutic targets for PTC is clinically crucial. In this study, we performed a multiomics analysis that identified a subset of CD36+ proinflammatory macrophages within the tumor microenvironment of PTC. The recruitment of CD36+ macrophages to premalignant regions strongly correlated with unfavorable outcomes in PTC, and the presence of tumor-infiltrating CD36+ macrophages was determined to be a risk factor for recurrence. The CD36+ macrophages exhibited interactions with metabolically active ZCCHC12+ tumor cells. By secreting SPP1, the CD36+ macrophages activated the PI3K-AKT signaling pathway, thereby promoting proliferation of the cancer cells. Dysregulation of iodine metabolism was closely related to the acquisition of the pro-inflammatory phenotype in macrophages. Iodine supplementation inhibited the activation of proinflammatory signaling and impeded the development of CD36+ macrophages by enhancing DUSP2 expression. Overall, our findings shed light on the intricate cross-talk between CD36+ macrophages and ZCCHC12+ tumor cells, providing valuable insights for the treatment and prognosis of PTC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1621-1639"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043866","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 Single-Cell Analysis of the NK-Cell Landscape Reveals That Dietary Restriction Boosts NK-Cell Antitumor Immunity via Eomesodermin.","authors":"Junming He, Donglin Chen, Wei Xiong, Yuande Wang, Shasha Chen, Meixiang Yang, Zhongjun Dong","doi":"10.1158/2326-6066.CIR-23-0944","DOIUrl":"10.1158/2326-6066.CIR-23-0944","url":null,"abstract":"<p><p>Abnormal metabolism in tumor cells represents a potential target for tumor therapy. In this regard, dietary restriction (DR) or its combination with anticancer drugs is of interest as it can impede the growth of tumor cells. In addition to its effects on tumor cells, DR also plays an extrinsic role in restricting tumor growth by regulating immune cells. NK cells are innate immune cells involved in tumor immunosurveillance. However, it remains uncertain whether DR can assist NK cells in controlling tumor growth. In this study, we demonstrate that DR effectively inhibits metastasis of melanoma cells to the lung. Consistent with this, the regression of tumors induced by DR was minimal in mice lacking NK cells. Single-cell RNA sequencing analysis revealed that DR enriched a rejuvenated subset of CD27+CD11b+ NK cells. Mechanistically, DR activated a regulatory network involving the transcription factor Eomesodermin (Eomes), which is essential for NK-cell development. First, DR promoted the expression of Eomes by optimizing mTORC1 signaling. The upregulation of Eomes revived the subset of functional CD27+CD11b+ NK cells by counteracting the expression of T-bet and downstream Zeb2. Moreover, DR enhanced the function and chemotaxis of NK cells by increasing the accessibility of Eomes to chromatin, leading to elevated expression of adhesion molecules and chemokines. Consequently, we conclude that DR therapy enhances tumor immunity through nontumor autonomous mechanisms, including promoting NK-cell tumor immunosurveillance and activation.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1508-1524"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987431","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 CAR-NK Cells with Tolerance to H2O2 and Hypoxia Can Suppress Postoperative Relapse of Triple-Negative Breast Cancers.","authors":"Yan Liu, Jiahui Chen, Jia Tian, Yu Hao, Xinxing Ma, Yehui Zhou, Liangzhu Feng","doi":"10.1158/2326-6066.CIR-23-1017","DOIUrl":"10.1158/2326-6066.CIR-23-1017","url":null,"abstract":"<p><p>Surgical resection is a primary treatment option for patients with triple-negative breast cancer (TNBC), but it is associated with a high rate of postoperative local and metastatic relapse. Although chimeric antigen receptor-engineered NK (CAR-NK) cell therapy can specifically recognize and eradicate tumor cells, its therapeutic potency toward TNBCs is markedly suppressed by the hostile tumor microenvironment, which restricts the infiltration, survival, and effector functions of CAR-NK cells inside tumor masses. In this study, HER1-overexpressing TNBC-targeted CAR-NK (HER1-CAR-NK) cells were genetically engineered with catalase to endow them with tolerance toward the high levels of oxidative stress and hypoxia inside TNBC tumors through the catalytic decomposition of hydrogen peroxide, which is a principle reactive oxygen species inside tumors, into O2. We refer to these cells as HER1-CAR-CAT-NK cells. Upon intratumoral fixation with an injectable alginate hydrogel, HER1-CAR-CAT-NK cells enabled sustained tumor hypoxia attenuation and exhibited markedly enhanced persistence and effector functions inside TNBC tumors. As a result, locoregional HER1-CAR-CAT-NK cell therapy not only inhibited the growth of local primary residual tumors but also elicited systemic antitumor activity to suppress the growth of distant tumors. This study highlights that genetic engineering of HER1-CAR-NK cells with catalase is a promising strategy to suppress the postoperative local and distant relapse of TNBC tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1574-1588"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632721","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":"The CCR6-CCL20 Axis Promotes Regulatory T-cell Glycolysis and Immunosuppression in Tumors.","authors":"Ayush Pant, Aanchal Jain, Yiyun Chen, Kisha Patel, Laura Saleh, Stephany Tzeng, Ryan T Nitta, Liang Zhao, Caren Yu-Ju Wu, Maria Bederson, William Lee Wang, Brandon Hwa-Lin Bergsneider, John Choi, Ravi Medikonda, Rohit Verma, Kwang Bog Cho, Lily H Kim, Jennifer E Kim, Eli Yazigi, Si Yeon Lee, Sakthi Rajendran, Prajwal Rajappa, Crystal L Mackall, Gordon Li, Betty Tyler, Henry Brem, Drew M Pardoll, Michael Lim, Christopher M Jackson","doi":"10.1158/2326-6066.CIR-24-0230","DOIUrl":"10.1158/2326-6066.CIR-24-0230","url":null,"abstract":"<p><p>Regulatory T cells (Treg) are important players in the tumor microenvironment. However, the mechanisms behind their immunosuppressive effects are poorly understood. We found that CCR6-CCL20 activity in tumor-infiltrating Tregs is associated with greater glycolytic activity and ablation of Ccr6 reduced glycolysis and lactic acid production while increasing compensatory glutamine metabolism. Immunosuppressive activity toward CD8+ T cells was abrogated in Ccr6-/- Tregs due to reduction in activation-induced glycolysis. Furthermore, Ccr6-/- mice exhibited improved survival across multiple tumor models compared to wild-type mice and Treg and CD8+ T-cell depletion abrogated the improvement. In addition, Ccr6 ablation further promoted the efficacy of anti-PD-1 therapy in a preclinical glioma model. Follow-up knockdown of Ccl20 with siRNA also demonstrated improvement in antitumor efficacy. Our results unveil CCR6 as a marker and regulator of Treg-induced immunosuppression and identify approaches to target the metabolic determinants of Treg immunosuppressive activity.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1542-1558"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916166","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}