title: Tumor antigen-specific CD8+T cells are negatively regulated by PD-1 and Tim-3 in human gastric cancer.
abstract: Cytotoxic CD8 T lymphocytes that are present in tumors and capable of recognizing tumor epitopes are nevertheless generally important in eliciting tumor rejection. NY-ESO-1 is a major target of CD8+T cell recognition in gastric cancer (GC) and is among the most immunogenic tumor antigens defined to date. Thus, identifying the immune escape mechanisms responsible for inducing tumor-specific CD8+T cell dysfunction may reveal effective strategies for immunotherapy. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8+T cells derived from peripheral blood lymphocytes (PBLs) and tumor-associated lymphocytes (TALs) of GC patients. Here, we report that Tim-3 expression defines a subpopulation of PD-1+exhausted NY-ESO-1-specific CD8+T cell and PD-1+Tim-3+CD8+T cells represented the largest subset of NY-ESO-1-specific CD8+T cells in GC patients. Functionally, CD8+PD-1+Tim-3+T cells were more impaired in IFN-γ, TNF-α and IL-2 production compared with PD-1+Tim-3-or PD-1-Tim-3-subsets. Dual blockade of Tim-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8+T cells could potentially be improved by therapeutic targeting of these inhibitory receptors, indicating that antitumor function of NY-ESO-1-specific CD8+T cells could potentially be improved by therapeutic targeting of these inhibitory receptors.
authors.affiliation: Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine, The Chinese Academy of Medical Sciences Tumor Hospital, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Agricultural Science Research Institute, Guangzhou Zengcheng District, China.
authors.forename: Daxing
authors.initials: D
authors.lastname: Yao
authors.affiliation: Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China.
authors.forename: Jingpo
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China.
authors.forename: Caiting
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China. Electronic address: ljwgirl361@163.com.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Liu
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D000068884:Immunosenescence; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D009367:Neoplasm Staging; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000276:immunology* / Q000473:pathology; D019139:Tumor Escape
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: CD8(+) T cells; PD-1; Tim-3; Tumor-associated lymphocytes