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

  • Kim, Hye Ryun1
  • Park, Hyo Jin2
  • Son, Jimin2
  • Lee, Jin Gu1
  • Chung, Kyung Young1
  • Cho, Nam Hoon3
  • Shim, Hyo Sup3
  • Park, Seyeon2
  • Kim, Gamin1
  • In Yoon, Hong3
  • Kim, Hyun Gyung4
  • Jung, Yong Woo4
  • Cho, Byoung Chul1
  • Park, Seong Yong1
  • Rha, Sun Young1
  • Ha, Sang-Jun2
  • 1 Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-Gu, Seoul, 120-752, South Korea , Seoul (South Korea)
  • 2 Yonsei University, Seoul, South Korea , Seoul (South Korea)
  • 3 Yonsei University College of Medicine, Seoul, South Korea , Seoul (South Korea)
  • 4 Korea University, Sejong, South Korea , Sejong (South Korea)
Published Article
Journal for ImmunoTherapy of Cancer
Springer (Biomed Central Ltd.)
Publication Date
Dec 04, 2019
DOI: 10.1186/s40425-019-0785-8
Springer Nature


BackgroundRegulatory T (Treg) cells have an immunosuppressive function in cancer, but the underlying mechanism of immunosuppression in the tumor microenvironment (TME) is unclear.MethodsWe 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.ResultsCD8+, 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.ConclusionsWe 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.

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