Abstract
Advances in cancer immunotherapy have transformed cancer care and realized unprecedented responses in many patients. The growing arsenal of novel therapeutics - including immune checkpoint inhibition (ICI), adoptive T cell therapies (ACTs), and cancer vaccines - reflects the success of cancer immunotherapy. The therapeutic benefits of these treatment modalities are generally attributed to the enhanced quantity and quality of antitumor CD8(+) T cell responses. Nevertheless, CD4(+) T cells are now recognized to play key roles in both the priming and effector phases of the antitumor immune response. In addition to providing T cell help through co-stimulation and cytokine production, CD4(+) T cells can also possess cytotoxicity either directly on MHC class II-expressing tumor cells or to other cells within the tumor microenvironment (TME). The presence of specific populations of CD4(+) T cells, and their intrinsic plasticity, within the TME can represent an important determinant of clinical response to immune checkpoint inhibitors, vaccines, and chimeric antigen receptor (CAR) T cell therapies. Understanding how the antitumor functions of specific CD4(+) T cell types are induced while limiting their protumorigenic attributes will enable more successful immunotherapies.