Differentiation and Regulation of T_H Cells: A Balancing Act for Cancer Immunotherapy

Current success of immunotherapy in cancer has drawn attention to the subsets of T_H cells in the tumor which are critical for activation of anti-tumor response either directly by themselves or by stimulating cytotoxic T cell activity. However, presence of immunosuppressive pro-tumorigenic T_H subsets in the tumor milieu further contributes to the complexity of regulation of T_H cell-mediated immune response. In this review, we present an overview of the multifaceted positive and negative effects of T_H cells, with an emphasis on regulation of different T_H cell subtypes by various immune cells, and how a delicate balance of contradictory signals can influence overall success of cancer immunotherapy. We focus on the regulatory network that encompasses dendritic cell-induced activation of CD4⁺ T_H1 cells and subsequent priming of CD8⁺ cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic T_H2 cell activity. We further discuss how other tumor infiltrating immune cells such as immunostimulatory T_H9 and T_fh cells, immunosuppressive T_reg cells, and the duality of T_H17 function contribute to tip the balance of anti- vs pro-tumorigenic T_H responses in the tumor. We highlight the developing knowledge of CD4⁺ T_H1 immune response against neoantigens/oncodrivers, impact of current immunotherapy strategies on CD4⁺ T_H1 immunity, and how opposing action of T_H cell subtypes can be explored further to amplify immunotherapy success in patients. Understanding the nuances of CD4⁺ T_H cells regulation and the molecular framework undergirding the balancing act between anti- vs pro-tumorigenic T_H subtypes is critical for rational designing of immunotherapies that can bypass therapeutic escape to maximize the potential of immunotherapy.