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(H)1 cells and subsequent priming of CD8(+) cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic T(H)2 cell activity. We further discuss how other tumor infiltrating immune cells such as immunostimulatory T(H)9 and T(fh) cells, immunosuppressive T(reg) cells, and the duality of T(H)17 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(H)1 immune response against neoantigens/oncodrivers, impact of current immunotherapy strategies on CD4(+) T(H)1 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.