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

• Published in: Oncotarget 2015-10, Vol.6 (32), p.32426-32438
• Main Authors: Yu, Zhe, Tan, Zhiwu, Lee, Boon Kiat, Tang, Jiansong, Wu, Xilin, Cheung, Ka-Wai, Lo, Nathan Tin Lok, Man, Kwan, Liu, Li, Chen, Zhiwei
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Apoptosis; Cancer Vaccines - administration & dosage; Cell Line; Coculture Techniques; Cytotoxicity, Immunologic; Female; Hepatitis A Virus Cellular Receptor 2; HIV Core Protein p24 - genetics; HIV Core Protein p24 - immunology; HIV-1 - genetics; HIV-1 - metabolism; Immunization; Immunotherapy, Adoptive; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mesothelioma - genetics; Mesothelioma - immunology; Mesothelioma - metabolism; Mesothelioma - pathology; Mesothelioma - therapy; Mesothelioma, Malignant; Mice, Inbred BALB C; Mice, SCID; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Research Paper: Immunology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Time Factors; Transfection; Tumor Escape; Vaccines, DNA - administration & dosage; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5856

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.