CD200+ cytotoxic T lymphocytes in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy

  • Sci Transl Med. 2023 Jan 18;15(679):eabn5029. doi: 10.1126/scitranslmed.abn5029.
Xinxin Wang  1 ,  Haoran Zha  1  2 ,  Wei Wu  3 ,  Ting Yuan  1 ,  Shuanglong Xie  1 ,  Zheng Jin  4 ,  Haixia Long  1 ,  Fei Yang  1 ,  Zhongyu Wang  1 ,  Anmei Zhang  1 ,  Jianbao Gao  1 ,  Ying Jiang  2 ,  Lujing Wang  1 ,  Chunyan Hu  1 ,  Yisong Y Wan  5 ,  Qi-Jing Li  6 ,  Alistair L J Symonds  7 ,  Qingzhu Jia  1 ,  Bo Zhu  1
Affiliations
  • 1. Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P. R. China.
  • 2. Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing 100088, P. R. China.
  • 3. Cardiothoracic Surgery Department, Southwest Hospital, Third Military Medical University, Chongqing 400037, P. R. China.
  • 4. Research Institute, GloriousMed Clinical Laboratory (Shanghai) Co. Ltd., 201318, P. R. China.
  • 5. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 6. Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
  • 7. Blizard Institute, Barts and London School of Medicine and Dentistry, University of London, London, E1 2AT UK.
PMID: 36652534 DOI: 10.1126/scitranslmed.abn5029
Abstract

Anti-PD-1/PD-L1 therapy, either by anti-PD-1 antibody or anti-PD-L1 antibody, has efficacy by reinvigorating tumor-infiltrating CD8+ T cells in a subset of patients with Cancer, but it has unequal effects on heterogeneous CD8+ T cell populations. Hence, the subset crucial to efficacious PD-1 blockade therapy remains elusive. Here, we found an increase in tumor-infiltrating CD200+ cytotoxic T lymphocytes (CTLs) upon PD-1/PD-L1 blockade, with higher proportions of CD200+ T cells positively related to a favorable clinical outcome to anti-PD-1/PD-L1 therapy in three independent cohorts of patients with Cancer. Using multiple mouse tumor models, we demonstrated that CD200+ CTLs are essential for efficacious anti-PD-L1 therapy. Mechanistically, we observed a unique chromatin landscape in CD200+ CTLs and found that these cells are enriched for tumor antigen-specific CTLs and have antitumor effector functions. Coinoculation of CD200+ CTLs with tumor cells led to robust tumor regression in two transplanted mouse models. Clinically, we found that infiltration of CD200+ CTLs into tumors could predict immunotherapy efficacy in six patient cohorts. Together, our findings reveal that CD200+ CTLs in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy and could serve as a predictor of successful immunotherapy in the clinic.

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