AUTHOR=Basu Amrita , Ramamoorthi Ganesan , Albert Gabriella , Gallen Corey , Beyer Amber , Snyder Colin , Koski Gary , Disis Mary L. , Czerniecki Brian J. , Kodumudi Krithika 

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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.669474

DOI=10.3389/fimmu.2021.669474

ISSN=1664-3224

ABSTRACT=<p>Current success of immunotherapy in cancer has drawn attention to the subsets of T<sub>H</sub> 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<sub>H</sub> subsets in the tumor milieu further contributes to the complexity of regulation of T<sub>H</sub> cell-mediated immune response. In this review, we present an overview of the multifaceted positive and negative effects of T<sub>H</sub> cells, with an emphasis on regulation of different T<sub>H</sub> 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<sup>+</sup> T<sub>H</sub>1 cells and subsequent priming of CD8<sup>+</sup> cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic T<sub>H</sub>2 cell activity. We further discuss how other tumor infiltrating immune cells such as immunostimulatory T<sub>H</sub>9 and T<sub>fh</sub> cells, immunosuppressive T<sub>reg</sub> cells, and the duality of T<sub>H</sub>17 function contribute to tip the balance of anti- vs pro-tumorigenic T<sub>H</sub> responses in the tumor. We highlight the developing knowledge of CD4<sup>+</sup> T<sub>H</sub>1 immune response against neoantigens/oncodrivers, impact of current immunotherapy strategies on CD4<sup>+</sup> T<sub>H</sub>1 immunity, and how opposing action of T<sub>H</sub> cell subtypes can be explored further to amplify immunotherapy success in patients. Understanding the nuances of CD4<sup>+</sup> T<sub>H</sub> cells regulation and the molecular framework undergirding the balancing act between anti- vs pro-tumorigenic T<sub>H</sub> subtypes is critical for rational designing of immunotherapies that can bypass therapeutic escape to maximize the potential of immunotherapy.</p>