Tailored Tumor Immunogenicity Reveals Regulation of CD4 and CD8 T Cell Responses against Cancer

Abstract

CD4 and CD8 T cells play a pivotal role in controlling tumor growth. However, the interplay of both cell types and their role in tumor suppression still remain elusive. In this study, we investigated the regulation of CD4 and CD8 T cell responses to different classes of tumor-specific antigens in liver cancer mouse models. Tumors were induced in p19Arf-deficient mice by hydrodynamic injection of transposon plasmids encoding NrasG12V and pre-defined tumor antigens. This allowed for assessing the regulation of tumor-specific CD4 and CD8 T cell responses. We showed that MHC class I tumor immunogenicity was essential to trigger tumor-directed CD4 T cells. Tumor-specific CD8 T cell responses arose independently of CD4 T cells, but they required Th1-polarized CD4 T cells for efficient tumor suppression. Our results further indicate that the immune system is incapable of eliciting sufficient numbers of T cells directed against antigens derived from immunoedited tumors, which consequently leads to a lack of T-cell-mediated tumor suppression in untreated hosts.

Keywords: CD4 T cells; CD8 T cells; T cell regulation; cancer immunosurveillance; cancer mouse model; immune responses to cancer; immunoediting; neoepitopes; oncogenic ras; senescence surveillance.