Abstract
Current success of immunotherapy in cancer has drawn attention to the subsets of TH 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 TH subsets in the tumor milieu further contributes to the complexity of regulation of TH cell-mediated immune response. In this review, we present an overview of the multifaceted positive and negative effects of TH cells, with an emphasis on regulation of different TH 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+ TH1 cells and subsequent priming of CD8+ cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic TH2 cell activity. We further discuss how other tumor infiltrating immune cells such as immunostimulatory TH9 and Tfh cells, immunosuppressive Treg cells, and the duality of TH17 function contribute to tip the balance of anti- vs pro-tumorigenic TH responses in the tumor. We highlight the developing knowledge of CD4+ TH1 immune response against neoantigens/oncodrivers, impact of current immunotherapy strategies on CD4+ TH1 immunity, and how opposing action of TH cell subtypes can be explored further to amplify immunotherapy success in patients. Understanding the nuances of CD4+ TH cells regulation and the molecular framework undergirding the balancing act between anti- vs pro-tumorigenic TH subtypes is critical for rational designing of immunotherapies that can bypass therapeutic escape to maximize the potential of immunotherapy.
Highlights
Amrita Basu 1, Ganesan Ramamoorthi 1, Gabriella Albert 1, Corey Gallen 1, Amber Beyer 1, Colin Snyder 1, Gary Koski 2, Mary L
We focus on the regulatory network that encompasses dendritic cellinduced activation of CD4+ TH1 cells and subsequent priming of CD8+ cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic TH2 cell activity
While CD8+ cytotoxic T lymphocyte (CTL) function has been explored extensively in recent years in the context of immunotherapy [3], research shows the crucial role of CD4+ T helper (TH) cells and its interaction with dendritic cells (DC) to transmit necessary molecular help that stimulates CTL function [4]
Summary
CD4+ regulatory T (Treg) cells exhibit critical roles in maintaining self-tolerance and preventing various autoimmune diseases. Conventional DC activating CD4+ T cells is a controversial topic where recent studies have implicated cDC1 as being capable of activating CD4+ T cell responses in cancer [2, 61, 64, 71, 72]; previously it has been understood that cDC1 secrete lower levels of IL-12 in comparison to cDC2, and cDC2 are recognized as the predominant activators of CD4+ T cell anti-tumor immunity [23, 64, 67, 72] This is in line with observations demonstrating that cDC2 are better equipped for CD4+ T cell differentiation due to preferential expression of MHC-II [64, 72, 73]. Significance of DC differentiation and antigen exposure on TH cell polarization has been further highlighted in a study by Khayrullina et al as DC differentiated in presence of prostaglandin E2 promotes an IL17-producing TH17 phenotype by inducing a modified IL-12/IL23 balance and inhibition of TH1/TH2 polarization, both in vitro and in vivo
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