Inflammatory dendritic cells restrain CD11b+CD4+ CTLs via CD200R in human NSCLC
Mingjie Lin,
Di Chen,
Zheyu Shao,
Qinyuan Liu,
Zhixing Hao,
Zhongwei Xin,
Yongyuan Chen,
Wenxuan Wu,
Xiaoke Chen,
Teng He,
Dang Wu,
Pin Wu
Affiliations
Mingjie Lin
Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Di Chen
Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Zheyu Shao
Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Qinyuan Liu
Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Zhixing Hao
Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Zhongwei Xin
Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Yongyuan Chen
Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Wenxuan Wu
Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Xiaoke Chen
Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Teng He
Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Infectious Disease, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Dang Wu
Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Corresponding author
Pin Wu
Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Corresponding author
Summary: CD4+ cytotoxic T lymphocytes (CD4+ CTLs) are suggested to play a crucial role in inflammatory diseases, including cancer, but their characteristics in human non-small cell lung cancer (NSCLC) remain unknown. Here, using the cell surface marker CD11b, we identify CD11b+CD4+ CTLs as a cytotoxic subset of CD4+ T cells in multiple tissues of NSCLC patients. In addition, tumor-infiltrating CD11b+CD4+ CTLs show a dysfunctional phenotype with elevated expression of CD200 receptor (CD200R), a negatively immunomodulatory receptor. CD4+ regulatory T (Treg) cells restrain the anti-tumor role of CD11b+CD4+ CTLs via CD200. Mechanistically, inflammatory dendritic cells promote the CD200R expression of CD11b+CD4+ CTLs by secreting interleukin-1β (IL-1β). Finally, we demonstrate that CD200 blockade can revive the tumor-killing role of CD11b+CD4+ CTLs and prolong the survival of tumor-bearing mice. Taken together, our study identifies CD11b+CD4+ CTLs in NSCLC with decreased cytotoxicity that can be reinvigorated by CD200 blockade, suggesting that targeting CD200 is a promising immunotherapy strategy in NSCLC.
