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

 Hye Ryun Kim  ;  Hyo Jin Park  ;  Jimin Son  ;  Jin Gu Lee  ;  Kyung Young Chung  ;  Nam Hoon Cho  ;  Hyo Sup Shim  ;  Seyeon Park  ;  Gamin Kim  ;  Hong In Yoon  ;  Hyun Gyung Kim  ;  Yong Woo Jung  ;  Byoung Chul Cho  ;  Seong Yong Park  ;  Sun Young Rha  ;  Sang-Jun Ha 
Journal Title
Issue Date
Immune checkpoints ; Programmed cell death 1 receptor ; Regulatory T cells ; Tumor microenvironment
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.
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Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Kim, Gamin(김가민) ORCID logo https://orcid.org/0000-0001-8504-7921
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Park, Seong Yong(박성용) ORCID logo https://orcid.org/0000-0002-5180-3853
Shim, Hyo Sup(심효섭) ORCID logo https://orcid.org/0000-0002-5718-3624
Yoon, Hong In(윤홍인) ORCID logo https://orcid.org/0000-0002-2106-6856
Lee, Jin Gu(이진구)
Chung, Kyung Young(정경영)
Cho, Nam Hoon(조남훈) ORCID logo https://orcid.org/0000-0002-0045-6441
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
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