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

Oncotarget. 2015 Oct 20;6(32):32426-38. 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.

Keywords: CD8+T cells; Immune response; Immunity; Immunology and Microbiology Section; MDSCs; antigen spreading; mesothelioma; vaccination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology*
  • Antigens, Neoplasm / metabolism
  • Apoptosis
  • Cancer Vaccines / administration & dosage*
  • Cell Line
  • Coculture Techniques
  • Cytotoxicity, Immunologic*
  • Female
  • HIV Core Protein p24 / genetics
  • HIV Core Protein p24 / immunology
  • HIV-1 / genetics
  • HIV-1 / metabolism
  • Hepatitis A Virus Cellular Receptor 2
  • 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*
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism
  • Time Factors
  • Transfection
  • Tumor Escape
  • Vaccines, DNA / administration & dosage
  • Xenograft Model Antitumor Assays


  • 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