Antigen spreading-induced CD8+T cells confer protection against the lethal challenge of wild-type malignant mesothelioma by eliminating myeloid-derived suppressor cells

Abstract

// Zhe Yu 1,2,* , Zhiwu Tan 1,* , Boon Kiat Lee 1 , Jiansong Tang 1 , Xilin Wu 1 , Ka-Wai Cheung 1 , Nathan Tin Lok Lo 1 , Kwan Man 3 , Li Liu 1 and Zhiwei Chen 1,4 1 AIDS Institute and Department of Microbiology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China 2 Department of Orthopedic Surgery, Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, P.R. China 3 Department of Surgery and Centre for Cancer Research, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China 4 Research Center for Infection and Immunity, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China * These authors have contributed equally to this work Correspondence to: Zhiwei Chen, email: // Keywords : CD8+T cells, vaccination, mesothelioma, antigen spreading, MDSCs, Immunology and Microbiology Section, Immune response, Immunity Received : August 03, 2015 Accepted : September 06, 2015 Published : September 28, 2015 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.