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: Zhe Yu, Zhiwu Tan, Boon Kiat Lee, Jiansong Tang, Xilin Wu, Ka-Wai Cheung, Nathan Tin Lok Lo, Kwan Man, Li Liu, Zhiwei Chen
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 32 Pg. 32426-38 (Oct 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26431275 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• HAVCR2 protein, human
• HIV Core Protein p24
• Hepatitis A Virus Cellular Receptor 2
• Membrane Proteins
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Vaccines, DNA

Topics

• Animals
• Antigens, Neoplasm (immunology, metabolism)
• Apoptosis
• Cancer Vaccines (administration & dosage)
• Cell Line
• Coculture Techniques
• Cytotoxicity, Immunologic
• Female
• HIV Core Protein p24 (genetics, immunology)
• HIV-1 (genetics, metabolism)
• Hepatitis A Virus Cellular Receptor 2
• Immunization
• Immunotherapy, Adoptive
• Lung Neoplasms (genetics, immunology, metabolism, pathology, therapy)
• Lymphocyte Activation
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism)
• Membrane Proteins (immunology, metabolism)
• Mesothelioma (genetics, immunology, metabolism, pathology, therapy)
• Mesothelioma, Malignant
• Mice, Inbred BALB C
• Mice, SCID
• Programmed Cell Death 1 Receptor (genetics, immunology)
• T-Lymphocytes, Cytotoxic (immunology, metabolism)
• Time Factors
• Transfection
• Tumor Escape
• Vaccines, DNA (administration & dosage)
• Xenograft Model Antitumor Assays