Vaccine-elicited CD8⁺ T cells overcome immune suppressive environment to cure malignant mesothelioma in mice

Abstract

Malignant mesothelioma is an aggressive cancer with increasing incidence worldwide. Exposure to asbestos is believed to be the main mechanistic basis of malignant transformation of mesothelial cells. Despite decades of efforts, treatment options for this malignancy are still limited to traditional surgery and chemotherapy, which do not provide significant survival benefits, highlighting the importance of finding novel therapeutic and preventive approaches to fight mesothelioma. For this reason, we aimed to examine the efficacy of immunotherapy strategy using DNA vaccines targeting tumor-expressing antigens. Immunotherapy targeting tumor associated self-antigen WT1 with conventional and PD1-based DNA vaccines was unable to induce tumor regression or improved survival in a quantitative mouse malignant mesothelioma model due to insufficient levels of antigen-specific immune responses being elicited. While why PD1-based DNA vaccine does not improve self-antigen WT1-specific immune responses remains to be investigated, it becomes important to define the level of vaccine-elicited immune responses for protection.

To date, the immune correlates of vaccine-elicited immunity remains poorly understood for the prevention and eradication of malignant mesothelioma. With the development of a malignant mesothelioma mouse model stably expressing HIV-1 GAG model antigen, we utilized the remarkably enhanced antigen-specific T cell responses elicited from our PD1-based HIV-1 GAG p24 vaccine to define antitumor responses. It has been demonstrated in this study that vaccine-elicited host immunity not only achieved complete and long-lasting protection against murine mesothelioma cell challenges but also resulted in therapeutic eradication of pre-existing mesothelioma after four consecutive DNA vaccinations. Vaccine-elicited 〖CD8〗^+ T cells attributed primarily and dose-dependently to the protective efficacy in both preventive and therapeutic settings. Moreover, the consecutive vaccinations activated polyfunctional 〖CD8〗^+ T effector cells via T-bet and Eomes-mediated pathways, leading to the rejection of mesothelioma by releasing inflammatory IFN-γ and TNF-α in the vicinity of target cells and by triggering the TRAIL induced apoptosis. Importantly, the vaccination not only activated 〖CD8〗^+ T cells and maintained their effector function but also overcame immunosuppressive networks by downregulating inhibitory PD1 and Tim-3 molecule expression on 〖CD8〗^+ cells and reducing suppressor cells such as myeloid-derived suppressor cells (MDSCs) and Treg, leading to the shift of tumor immune oediting from progression to elimination.

Taken together, the generation of malignant mesothelioma mouse models in our study can enable targeting immunotherapy strategies to be evaluated in a quantitative way. Our data suggested that high frequency of vaccine-elicited 〖CD8〗^+ T cells could prevent and eradicate malignant mesothelioma. The activation of quantitatively and qualitatively enhanced CD8+ T cells caneliminate theimmune suppressive network contributing to the complete tumor rejection.