title: TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence.
abstract: Accumulating evidence suggests the immunosuppressive microenvironments created by malignant tumors represent a major obstacle for effective anti-tumor immunity. A better understanding of the suppressive mechanisms mediated by tumor microenvironments and the development of strategies to reverse the immune suppression are major challenges for the success of tumor immunotherapy. Here, we report that human tumor cells can induce senescence in naïve/effector T cells, exhibiting potent suppressive function in vitro and in vivo. We further show that tumor-derived endogenous cyclic adenosine monophosphate (cAMP) is responsible for the induction of T-cell senescence. Importantly, activation of TLR8 signaling in tumor cells can block the induction and reverse the suppression of senescent naïve and tumor-specific T cells in vitro and in vivo, resulting in enhanced anti-tumor immunity. These studies identify a novel mechanism of human tumor-mediated immune suppression and provide a new strategy to reverse tumor immunosuppressive effects for tumor immunotherapy.
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA Department of Laboratory Medicine, Women & Children's Health Care Hospital of Linyi, Linyi, China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Surgery, Division of General Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Eddy C
authors.initials: EC
authors.lastname: Hsueh
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Dou
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Mo
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Surgery, Division of General Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Varvares
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA gpeng@slu.edu.
authors.forename: Guangyong
authors.initials: G
authors.lastname: Peng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D016219:Immunotherapy, Adoptive; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D000242:Cyclic AMP
keywords: immunosenescence; regulatory T cells; toll‐like receptor; tumor immunity; tumor microenvironment