CD4+ T cells in antitumor immunity

Abstract

Advances in cancer immunotherapy have transformed cancer care and realized unprecedented responses in many patients. The growing arsenal of novel therapeutics - including immune checkpoint inhibition (ICI), adoptive T cell therapies (ACTs), and cancer vaccines - reflects the success of cancer immunotherapy. The therapeutic benefits of these treatment modalities are generally attributed to the enhanced quantity and quality of antitumor CD8⁺ T cell responses. Nevertheless, CD4⁺ T cells are now recognized to play key roles in both the priming and effector phases of the antitumor immune response. In addition to providing T cell help through co-stimulation and cytokine production, CD4⁺ T cells can also possess cytotoxicity either directly on MHC class II-expressing tumor cells or to other cells within the tumor microenvironment (TME). The presence of specific populations of CD4⁺ T cells, and their intrinsic plasticity, within the TME can represent an important determinant of clinical response to immune checkpoint inhibitors, vaccines, and chimeric antigen receptor (CAR) T cell therapies. Understanding how the antitumor functions of specific CD4⁺ T cell types are induced while limiting their protumorigenic attributes will enable more successful immunotherapies.

Keywords: CD4(+) T lymphocytes; antigen-presenting cells; cancer immunotherapy.

Figure 1:

The differentiation pathways of CD4+CTLs. Multiple subsets of CD4+ T cells can acquire cytotoxic capabilities through a combination of the following pathways: 1) TCR signal strength or duration can lead to downstream upregulation of EOMES-mediated cytotoxicity related genes; 2) 3) IL-2 signaling can augment CRTAM-mediated EOMES upregulation; 3) Type I IFN can signal through STAT2 to upregulate both T-BET and BLIMP-1, leading to upregulation of cytotoxic genes; and 4) Cytokines IL-2 and IL-15 can signal through STAT5 to upregulate BLIMP-1 independently of Type I IFN signaling.

Figure 2:. CD4⁺ T cells can exert their anti-tumor effects through both direct and indirect mechanisms.

A, Environmental cues facilitate CD4⁺ cytotoxic lymphocyte (CD4⁺CTL) differentiation through multiple pathways, including cytokine production, ligand expression, and TCR signal strength. Thus, CD4⁺CTL differentiation can be curated based on environmental needs. These pathways can work independently from one another, and potentially may synergize for optimal cytotoxic induction through FAS/FASL signaling, and cytotoxic granzyme (GZM) and perforin (PRF) secretion. B, many of the indirect anti-tumor functions of CD4⁺ T cells are though cytokine secretion, which can recruit and activate cytotoxic immune cells including macrophages (mf), dendritic cells (DC), B cells, and NK cells to induce tumor cell death.