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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.

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