Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox

Abstract

Cytotoxic T cells are important effectors of anti-tumor immunity. While tumor killing is ascribed to CD8⁺ T cell function, pre-clinical and clinical studies have identified intra-tumoral CD4⁺ T cells that possess cytotoxic programs and can directly kill cancer cells. Cytotoxic CD4⁺ T cells are found in other disease settings including infection and autoimmunity. Here, we review the phenotypic and functional characteristics of cytotoxic CD4⁺ T cells in non-cancer and cancer contexts. We conduct a comparative examination of cytolytic mechanisms of cytotoxic CD4⁺ T cells across disease states and synthesize features that define these cells independent of context. We discuss regulatory mechanisms driving ontogeny and effector function and evidence for the clinical relevance of cytotoxic CD4⁺ T cells in cancer. In this context, we highlight important gaps in understanding in the biology of cytotoxic CD4⁺ T cells as well as the potential use of these cells in immunotherapies for specific cancers.

Figure 1.. The ontogeny and regulation of cytotoxic CD4⁺ T cells in cancer

(A) A schematic of known CD4⁺ T cell functional subtypes, the cytokines that promote their differentiation, and master transcription factors (TFs) involved in their specification. As indicated, cytotoxic CD4⁺ T cells can arise from unpolarized Th0, Th1, or Th2 cells in response to IL-2 depending on the context; also, the contributions of the TFs RUNX3, TBET, BLIMP-1, and EOMES to specifying the cytotoxic CD4+ T cell state are also context-dependent, as discussed in the text. (B) Mechanisms that may contribute to activation of cytotoxic CD4⁺ T cells (red), anti-tumor cytotoxicity effector function (dark blue) including cytokines (light blue), as well as co-stimulatory (orange) or co-inhibitory (green) immune checkpoints are shown.

Figure 2.. Comparison of cytotoxic CD4⁺ T cell programs in cancer and non-cancer contexts

Expression of key transcripts in cytotoxic CD4⁺ T cells in human and murine cancer, as well as human viral (dengue), murine viral (adenovirus), and human aging. Comparisons were made based on inspection of single-cell transcriptomic data, with the exception of bulk microarray data for murine cancer. Specific references for each dataset, and the platforms used for single-cell sequencing, are indicated. Lighter shading and question marks indicate where findings are inconsistent between datasets (e.g., comparing various human cancers).