title: Targeting PD-1 and Tim-3 Pathways to Reverse CD8 T-Cell Exhaustion and Enhance Ex Vivo T-Cell Responses to Autologous Dendritic/Tumor Vaccines.
abstract: The paradoxical coexistence of spontaneous tumor antigen-specific immune response with progressive disease in cancer patients need to dissect the molecular pathways involved in tumor-induced T-cell dysfunction or exhaustion. Programmed cell death 1 (PD-1) has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1-PD-L1 interactions has been shown to partially restore T-cell function. We have found that T-cell immunoglobulin mucin (Tim) 3 is expressed on CD8+ tumor-infiltrating lymphocytes (TILs) isolated from patients with colorectal cancer. All T-cell immunoglobulin mucin 3 (Tim-3+) TILs coexpress PD-1, and Tim-3+ PD-1+ CD8+ TILs represent the predominant fraction of Tcells infiltrating tumors. Tim-3+PD-1+ CD8+ TILs exhibit the most severe exhausted phenotype as defined by failure to produce cytokines, such as interferon-γ, tumor necrosis factor-α, and interleukin-2. We further find that combined targeting of the Tim-3 and PD-1 pathways increased the frequencies of not only interferon-γ and tumor necrosis factor-α but also frequencies of proliferating tumor antigen-specific CD8+ T cells than targeting either pathway alone. A concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. Collectively, our findings support the use of Tim-3-Tim-3L blockade together with PD-1-PD-L1 blockade to reverse tumor-induced T-cell exhaustion/dysfunction in patients with colorectal cancer.
authors.affiliation: *Department of Oncology, Beijing Biohealthcare Biotechnology Co. Ltd †Department of Oncology, Beijing Tongren Hospital, Capital Medical University ‡Department of Interventional Therapy Center, Beijing Shunyi District Hospital, Beijing, China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Liu
authors.forename: Shurong
authors.initials: S
authors.lastname: Zhang
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Hu
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Yang
authors.forename: Jingpo
authors.initials: J
authors.lastname: Li
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Lijuan
authors.initials: L
authors.lastname: Deng
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Jiang
authors.forename: Xu
authors.initials: X
authors.lastname: Lu
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000276:immunology / Q000628:therapy*; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D019496:Cancer Vaccines; D016207:Cytokines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor