{"title":"Selective depletion of CCR8+Treg cells enhances anti-tumor immunity of cytotoxic T cells in lung cancer via dendritic cells.","authors":"Peixin Chen, Haowei Wang, Zhuoran Tang, Jinpeng Shi, Lei Cheng, Chao Zhao, Xuefei Li, Caicun Zhou","doi":"10.1016/j.jtho.2025.02.029","DOIUrl":null,"url":null,"abstract":"<p><p>Accumulation of regulatory T (Treg) cells, an immunosuppressive population, limits the efficacy of immunotherapy in non-small cell lung cancer (NSCLC). C-C Motif Chemokine Receptor 8 (CCR8) is selectively expressed in tumor-infiltrating Treg cells and, thus considered an ideal target. Across four NSCLC-bearing mice models, the combination of CCR8 antibody and programmed cell death protein-1 (PD1) inhibitor significantly reduced tumor growth without obvious mouse body weight drops and systemic cytokine storm. The single-cell RNA and T-cell receptor sequencing analysis demonstrated that anti-CCR8 therapy synergizes with PD1 blockade by remodeling the tumor microenvironment and disrupting CCR8+Treg - CCL5+ dendritic cells (DC) interaction. Mechanistically, therapeutic depletion of CCR8+Treg cells combined with PD1 inhibitor extremely increased interleukin-12 secretion by the JAK-STAT pathway activation on CCL5+ DCs, thereby promoting cytotoxic activity of CD8+ T cells. The therapeutic potential of the CCR8 antibody LM-108 in combination with immunotherapy was observed in clinical patients with advanced NSCLC. Overall, CCR8 expression on tumor-infiltrating Treg cells is correlated with immunosuppressive function on DCs and CD8+ T cells, thus impeding anti-tumor immunity.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0000,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Thoracic Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jtho.2025.02.029","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Accumulation of regulatory T (Treg) cells, an immunosuppressive population, limits the efficacy of immunotherapy in non-small cell lung cancer (NSCLC). C-C Motif Chemokine Receptor 8 (CCR8) is selectively expressed in tumor-infiltrating Treg cells and, thus considered an ideal target. Across four NSCLC-bearing mice models, the combination of CCR8 antibody and programmed cell death protein-1 (PD1) inhibitor significantly reduced tumor growth without obvious mouse body weight drops and systemic cytokine storm. The single-cell RNA and T-cell receptor sequencing analysis demonstrated that anti-CCR8 therapy synergizes with PD1 blockade by remodeling the tumor microenvironment and disrupting CCR8+Treg - CCL5+ dendritic cells (DC) interaction. Mechanistically, therapeutic depletion of CCR8+Treg cells combined with PD1 inhibitor extremely increased interleukin-12 secretion by the JAK-STAT pathway activation on CCL5+ DCs, thereby promoting cytotoxic activity of CD8+ T cells. The therapeutic potential of the CCR8 antibody LM-108 in combination with immunotherapy was observed in clinical patients with advanced NSCLC. Overall, CCR8 expression on tumor-infiltrating Treg cells is correlated with immunosuppressive function on DCs and CD8+ T cells, thus impeding anti-tumor immunity.
期刊介绍:
Journal of Thoracic Oncology (JTO), the official journal of the International Association for the Study of Lung Cancer,is the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies.The readship includes epidemiologists, medical oncologists, radiation oncologists, thoracic surgeons, pulmonologists, radiologists, pathologists, nuclear medicine physicians, and research scientists with a special interest in thoracic oncology.