To Investigate the Role of Helps from CD4+T Cells in the Restoration of Dysfunctions of Anti-Tumor CD8+T Cells in a Murine Hepatoma Model

Accumulating evidence in recent years has clearly shown dysfunctional CD8+T cells play an important role in the immune escape of tumor. Furthermore, to restore the functions of these dysfunctional CD8+T cells become one of the strategies for the tumor immunotherapy. In previous studies, we had shown the hepatoma could secrete CCL5 and attract the CCR5 expressed Treg cells to accumulate in the tumor microenvironment. However, there was more non-Foxp3 CD4+T cells accumulate in the tumor microenvironment. In addition, we had also shown the tumor-specific CD8+T cells in the tumor microenvironment were easily to be apoptotic. However, recent data had shown that the help from CD4+T cells could rescue the dysfunctional CD8+T cells in a murine LCMV chronic viral infection model. The helps from CD4+T cells on the functions of CD8+T cells had not been explored in the tumor immune responses. Therefore, we proposed a hypothesis that helps from CD4+T cells could also rescue these dysfucntional CD8+T cells in hepatoma. Current proposal is aiming to characterize the role of helps from CD4+T cells in restoration of exhaustive/apoptotic hepatoma-specific CD8+T cells. We had already set up a tumor-antigen specific TCR transgenic CD4 and CD8+T cells mice system. By this mice system, we will achieve the current proposal by accomplish the following aims: Specific Aim I: to investigate the phenotype of tumor-antigen specific CD8+T cells in different compartments in tumor-bearing mice. Specific Aim II: to study the phenotype of tumor-antigen specific non-Treg CD4+T cells in different compartments in tumor-bearing mice. Specific Aim III: to explore the contribution of helps of CD4+T cells to the survival/effector functions of tumor-antigen specific CD8+T cells in the tumor microenvironment and the control of tumor growth. We expect, by these approaches, we could provide strong evidence to incorporate the helps form CD4+T cells into the tumor immunotherapy for hepatoma. We expect the results from this proposal could give a paradigm-shift impact on the current immunotherapy for cancer.

Project ID:PC10301-0557
External Project ID:NSC102-2314-B182A-119-MY2