The role of CD4(+) T cells in tumor and chronic viral immune responses

Immunotherapies are mainly aimed to promote a CD8(+) T cell response rather than a CD4(+) T cell response as cytotoxic T lymphocytes (CTLs) can directly kill target cells. Recently, CD4(+) T cells have received more attention due to their diverse roles in tumors and chronic viral infections. In antitumor and antichronic viral responses, CD4(+) T cells relay help signals through dendritic cells to indirectly regulate CD8(+) T cell response, interact with B cells or macrophages to indirectly modulate humoral immunity or macrophage polarization, and inhibit tumor blood vessel formation. Additionally, CD4(+) T cells can also exhibit direct cytotoxicity toward target cells. However, regulatory T cells exhibit immunosuppression and CD4(+) T cells become exhausted, which promote tumor progression and chronic viral persistence. Finally, we also outline immunotherapies based on CD4(+) T cells, including adoptive cell transfer, vaccines, and immune checkpoint blockade. Overall, this review summarizes diverse roles of CD4(+) T cells in the antitumor or protumor and chronic viral responses, and also highlights the immunotherapies based on CD4(+) T cells, giving a better understanding of their roles in tumors and chronic viral infections.