Tumor microenvironment dictates regulatory T cell phenotype: Upregulated immune checkpoints reinforce suppressive function

Journal for ImmunoTherapy of Cancer

Hyo Jin Park¹  Sang-Jun Ha¹  Seyeon Park¹  Jimin Son¹  Hyo Sup Shim²  Nam Hoon Cho²  Yong Woo Jung³  Hyun Gyung Kim³  Hong In Yoon⁴  Seong Yong Park⁵  Kyung Young Chung⁵  Jin Gu Lee⁵  Byoung Chul Cho⁶  Hye Ryun Kim⁶  Gamin Kim⁶  Sun Young Rha⁶ 

[1] Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University;Department of Pathology, Yonsei University College of Medicine;Department of Pharmacy, Korea University;Department of Radiation Oncology, Yonsei University College of Medicine;Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine;Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine;

关键词: Tumor microenvironment;    Regulatory T cells;    Immune checkpoints;    Programmed cell death 1 receptor;   

DOI  :  10.1186/s40425-019-0785-8

来源: DOAJ

【 摘 要 】

Abstract Background Regulatory T (Treg) cells have an immunosuppressive function in cancer, but the underlying mechanism of immunosuppression in the tumor microenvironment (TME) is unclear. Methods We compared the phenotypes of T cell subsets, including Treg cells, obtained from peripheral blood, malignant effusion, and tumors of 103 cancer patients. Our primary focus was on the expression of immune checkpoint (IC)-molecules, such as programmed death (PD)-1, T-cell immunoglobulin and mucin-domain containing (TIM)-3, T cell Ig and ITIM domain (TIGIT), and cytotoxic T lymphocyte antigen (CTLA)-4, on Treg cells in paired lymphocytes from blood, peritumoral tissue, and tumors of 12 patients with lung cancer. To identify the immunosuppressive mechanisms acting on tumor-infiltrating Treg cells, we conducted immunosuppressive functional assays in a mouse model. Results CD8+, CD4+ T cells, and Treg cells exhibited a gradual upregulation of IC-molecules the closer they were to the tumor. Interestingly, PD-1 expression was more prominent in Treg cells than in conventional T (Tconv) cells. In lung cancer patients, higher levels of IC-molecules were expressed on Treg cells than on Tconv cells, and Treg cells were also more enriched in the tumor than in the peri-tumor and blood. In a mouse lung cancer model, IC-molecules were also preferentially upregulated on Treg cells, compared to Tconv cells. PD-1 showed the greatest increase on most cell types, especially Treg cells, and this increase occurred gradually over time after the cells entered the TME. PD-1 high-expressing tumor-infiltrating Treg cells displayed potent suppressive activity, which could be partially inhibited with a blocking anti-PD-1 antibody. Conclusions We demonstrate that the TME confers a suppressive function on Treg cells by upregulating IC-molecule expression. Targeting IC-molecules, including PD-1, on Treg cells may be effective for cancer treatment.

【 授权许可】

Unknown