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

Abstract

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.

Keywords: CD4; T helper; immunotherapy; neoantigen; tumor associated antigen.

Figure 1

CD4+ T cells development and their functional subsets in immunity. T cell receptor (TCR) signaling activation, co-stimulation and presence of specific cytokines milieu have been shown to stimulate naïve CD4⁺ T cells polarization and their differentiation into T_H1, T_H2, T_H9, T_H17, T_fh and T_reg cell subtypes. While T_H1, T_H9 and T_fh cells (green box) stimulate anti-tumor immune response, T_H2 and T_reg cells (red box) induce immunosuppressive protumorigenic response and a dual role of T_H17 cells contribute to the functional complexity of this network. Primary STAT signaling pathways and major transcription factors regulating CD4⁺ T cell subtype polarization and key effector cytokines secreted from each Th cell subtypes are depicted. Dendritic cells present tumor antigenic peptides to T_H1 cells via MHC class II molecule, leading to T_H1 immune response activation. IFN-γ and TNF-α secreted from activated T_H1 cells directly act on tumor cells and induce apoptosis, senescence, and proliferation arrest. In addition, T_H1 cells can upregulate NK cells and B cells activation to further strengthen anti-tumor immune responses. Activated T_H1 cells secrete IL-2 which mediates direct activation of CD8⁺ T cells expressing IL-2Rα and their proliferation and survival. In contrast, T_reg cells and T_H17 cells are known to exhibit an immunosuppressive microenvironment that promotes tumor progression.

Figure 2

Intratumoral balance of anti- vs pro-tumorigenic CD4⁺ T_H cells determine immune response outcome. Activation and downregulation of specific T_H cells modulate intratumoral balance of stimulatory and suppressive effectors and modulates tumor response to immunotherapy. Polarization and activation of T_H1, T_H9 and T_fh subtypes induce secretion of proinflammatory cytokines, and, coupled with simultaneously diminished activity of immunosuppressive T_H2 and T_reg cells, tip the balance towards anti-tumor immune response and induce tumor regression (left). On the contrary, heightened activity of the immunosuppressive populations and secretion of inhibitory cytokines, and concurrent downregulation of immunostimulatory T_H1, T_H9 and T_fh cells induce a protumorigenic microenvironment, resulting in disease progression (right). To shift the balance to either end of the equilibrium, a concerted effort by multiple T_H subtypes are necessary and may not be achieved by alteration in the functional state of a single T_H subtype.

Figure 3

Therapeutic targeting of tumor associated antigens and neoantigens activate anti- vs. protumorigenic CD4+ T_H cell subtypes. Therapeutic targeting of oncodrivers/TAA/self-antigens may stimulate tumor immune response differently than strategies involving neoantigens. (A) Intratumoral balance of anti- and protumorigenic CD4⁺ T_H immune cell population maintain the equilibrium of inflammatory (IFN-γ, TNF-α, IL-2, IL-6, IL-9, IL-21) and inhibitory cytokines (IL-4, IL-5, IL-10, TGF-β) in cancer cell and determine overall immune response to therapy. (B) When tumor cells express self-antigens/TAA/oncodrivers (blue spheres), due to low abundance and weak immunogenicity of these antigens, effective immunotherapy targeting these proteins may require a more extensive shift in the balance of anti- vs pro-tumor immune effector populations, including recruitment and activation of all anti-tumorigenic T_H1/T_H9/T_fh populations (green arrow) and suppression of all pro-tumorigenic T_H2/T_H17/T_reg/MDSC function (red arrow). Conversely, highly antigenic and abundant neoantigens (green spheres) may be sufficient to stimulate anti-tumor immune response either by (C) driving up infiltration and hyperactivation of primarilyT_H1, along with T_H9 and T_fh immunostimulatory response (green arrow) with minimal changes in the inhibitory immune cell function (grey arrow) or by (D) drastic downregulation of immunosuppressive response by T_H2/T_H17/T_reg/MDSC cells (red arrow) without a significant change in the immunostimulatory population of T_H1/T_H9/T_fh cells (grey arrow) (light green, T_H1; red, T_H2; orange, T_H9; blue, T_fh; dark green, T_H17; grey, T_reg; purple, MDSC).

Figure 4

CD4⁺ T cells in cancer immunotherapy. Immunotherapeutic strategies that activate CD4⁺ T cells and their downstream effector immune cells for cancer treatment are depicted. Therapeutic vaccination includes tumor antigenic peptides, viral vector-based vaccine and DNA based vaccine that can mediate CD4⁺ T cells immune responses. DC-based vaccines can prime CD4⁺ T cells and create signals to activate cytotoxic CD8⁺ T cells differentiation and anti-tumor function. Adoptive transfer of tumor specific CD4⁺ T cells is another attractive immunotherapy approach which helps to develop specific and strong anti-tumor immune reaction. Chimeric antigen receptors can also redirect CD4⁺ T cells and provide activation signals to recognize cancer cells to eliminate them. Blockade of immune checkpoints PD1, PD-L1 and CTLA4 by antibodies can prevent tumor associated immunosuppressive environment and enhance tumor specific CD4⁺ and CD8⁺ T cells immune responses.