title: Vaccine-elicited CD8+ T cells cure mesothelioma by overcoming tumor-induced immunosuppressive environment.
abstract: Eradicating malignant tumors by vaccine-elicited host immunity remains a major medical challenge. To date, correlates of immune protection remain unknown for malignant mesothelioma. In this study, we demonstrated that antigen-specific CD8(+) T-cell immune response correlates with the elimination of malignant mesothelioma by a model PD-1-based DNA vaccine. Unlike the nonprotective tumor antigen WT1-based DNA vaccines, the model vaccine showed complete and long-lasting protection against lethal mesothelioma challenge in immunocompetent BALB/c mice. Furthermore, it remained highly immunogenic in tumor-bearing animals and led to therapeutic cure of preexisting mesothelioma. T-cell depletion and adoptive transfer experiments revealed that vaccine-elicited CD8(+) T cells conferred to the protective efficacy in a dose-dependent way. Also, these CD8(+) T cells functioned by releasing inflammatory IFNγ and TNFα in the vicinity of target cells as well as by initiating TRAIL-directed tumor cell apoptosis. Importantly, repeated DNA vaccinations, a major advantage over live-vectored vaccines with issues of preexisting immunity, achieve an active functional state, not only preventing the rise of exhausted PD-1(+) and Tim-3(+) CD8(+) T cells but also suppressing tumor-induced myeloid-derived suppressive cells and Treg cells, with the frequency of antigen-specific CD8(+) T cells inversely correlating with tumor mass. Our results provide new insights into quantitative and qualitative requirements of vaccine-elicited functional CD8(+) T cells in cancer prevention and immunotherapy.
authors.affiliation: AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
authors.forename: Zhiwu
authors.initials: Z
authors.lastname: Tan
authors.affiliation: AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
authors.forename: Jingying
authors.initials: J
authors.lastname: Zhou
authors.affiliation: AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
authors.forename: Allen K L
authors.initials: AK
authors.lastname: Cheung
authors.affiliation: AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yu
authors.affiliation: AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
authors.forename: Ka-Wai
authors.initials: KW
authors.lastname: Cheung
authors.affiliation: AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Liang
authors.affiliation: AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
authors.forename: Boon Kiat
authors.initials: BK
authors.lastname: Lee
authors.affiliation: Department of Surgery and Centre for Cancer Research, The University of Hong Kong, Hong Kong SAR, P.R. China.
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.affiliation: AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China. Research Center for Infection and Immunity, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
authors.affiliation: AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China. Research Center for Infection and Immunity, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China. zchenai@hku.hk.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019496:Cancer Vaccines / Q000008:administration & dosage; D045744:Cell Line, Tumor; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology; D025721:WT1 Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D007166:Immunosuppressive Agents; D019444:Vaccines, DNA; D025721:WT1 Proteins; C583751:WT1 protein, human; D007371:Interferon-gamma