title: Antigen spreading-induced CD8+T cells confer protection against the lethal challenge of wild-type malignant mesothelioma by eliminating myeloid-derived suppressor cells.
abstract: A key focus in cancer immunotherapy is to investigate the mechanism of efficacious vaccine responses. Using HIV-1 GAG-p24 in a model PD1-based DNA vaccine, we recently reported that vaccine-elicited CD8+ T cells conferred complete prevention and therapeutic cure of AB1-GAG malignant mesothelioma in immunocompetent BALB/c mice. Here, we further investigated the efficacy and correlation of protection on the model vaccine-mediated antigen spreading against wild-type AB1 (WT-AB1) mesothelioma. We found that this vaccine was able to protect mice completely from three consecutive lethal challenges of AB1-GAG mesothelioma. Through antigen spreading these animals also developed tumor-specific cytotoxic CD8+ T cells, but neither CD4+ T cells nor antibodies, rejecting WT-AB1 mesothelioma. A majority of these protected mice (90%) were also completely protected against the lethal WT-AB1 challenge. Adoptive cell transfer experiments further demonstrated that antigen spreading-induced CD8+ T cells conferred efficacious therapeutic effects against established WT-AB1 mesothelioma and prevented the increase of exhausted PD-1+ and Tim-3+ CD8+ T cells. A significant inverse correlation was found between the frequency of functional PD1-Tim3- CD8+ T cells and that of MDSCs or tumor mass in vivo. Mechanistically, we found that WT-AB1 mesothelioma induced predominantly polymorphonuclear (PMN) MDSCs in vivo. In co-cultures with efficacious CD8+ T cells, a significant number of PMN-MDSCs underwent apoptosis in a dose-dependent way. Our findings indicate that efficacious CD8+ T cells capable of eliminating both tumor cells and MDSCs are likely necessary for fighting wild-type malignant mesothelioma.
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.|Department of Orthopedic Surgery, Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 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: 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: Boon Kiat
authors.initials: BK
authors.lastname: Lee
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: Jiansong
authors.initials: J
authors.lastname: Tang
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: Xilin
authors.initials: X
authors.lastname: Wu
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: Nathan Tin Lok
authors.initials: NT
authors.lastname: Lo
authors.affiliation: Department of Surgery and Centre for Cancer Research, LKS Faculty of Medicine, 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: Zhiwei
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis; D019496:Cancer Vaccines / Q000008:administration & dosage*; D002460:Cell Line; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D005260:Female; D016655:HIV Core Protein p24 / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2; D007114:Immunization; D016219:Immunotherapy, Adoptive; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D008654:Mesothelioma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000086002:Mesothelioma, Malignant; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D019139:Tumor Escape; D019444:Vaccines, DNA / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C448908:HAVCR2 protein, human; D016655:HIV Core Protein p24; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D019444:Vaccines, DNA
keywords: CD8+T cells; Immune response; Immunity; Immunology and Microbiology Section; MDSCs; antigen spreading; mesothelioma; vaccination