γδ T Cells: Crosstalk Between Microbiota, Chronic Inflammation, and Colorectal Cancer

Abstract

Increasing evidence suggests that intestinal microbiota dysbiosis and chronic inflammation contribute to colorectal cancer (CRC) development. γδ T cells represent a major innate immune cell population in the intestinal epithelium that is involved in the maintenance of gut homeostasis, inflammation regulation, and carcinogenesis. The important contributions of γδ T cells are (i) to perform a protective role in the context of barrier damage and pathogenic microorganism translocation; (ii) to exert either pro- or anti-inflammatory effects at different inflammatory stages; and (iii) to boost the crosstalk between immune cells and tumor microenvironment, inducing a cascade of suppressive immune responses. Understanding the crucial role of γδ T cells would enable us to manipulate these cells during the CRC sequence and improve the efficacy of tumor therapy.

Keywords: chronic inflammation; colorectal cancer; microbiota; tumor microenvironment; γδ T cells.

Figure 1

Schematic overview of the protective roles of γδ T cells in homeostasis maintenance and immune surveillance. (1) Physiologically, the crosstalk between microbiota, epithelial cells (ECs), and γδ T cells enhances barrier stabilization. (2) During acute inflammation, neutrophils are stimulated by IL-17 from γδ T cells, and recruited to eliminate pathogens. Meanwhile, microbe-activated circulating γδ T cells promote cytotoxic responses with Th1-committed αβ T cells and potentiate the release of calprotectin in an inducible T-cell co-stimulator ligand (ICOSL)/tumor necrosis factor α (TNF-α)-dependent manner. IEL, intraepithelial lymphocyte; MYD88, myeloid differentiation primary response 88; KC, keratinocyte-derived chemokine; CXCL, chemokine (C-X-C motif) ligand; MIP2α, macrophage inflammatory protein 2α; CCR, C-C motif chemokine receptor; TLR, toll-like receptor; IFN-γ, interferon γ; IL-17, interleukin-17.

Figure 2

The roles played by γδ T cells at different stages of colorectal cancer development. (1) During chronic inflammation, γδ T cells can limit excessive inflammatory response and maintain homeostasis by (a) removal of impaired epithelial cells; (b) secretion of protective IL-17; (c) enhancement of Gr-1⁺CD11b⁺ suppressor cell infiltration; and (d) regulation of αβ T cell functions. (2) At the initiation of tumor formation, circulating γδ T cells can recognize and kill cancer cells, but they are reprogrammed with cancer development. (3) At stages of tumor progression, IL-17 and granulocyte macrophage colony-stimulating factor (GM-CSF), produced by γδ T cells in response to IL-23 and transforming growth factor beta 1 (TGF-β1) from inflammatory dendritic cells (inf-DCs) and cancer cells, are essential for the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), consequently inducing a cascade of suppressive immune responses. CTLA4, cytotoxic T lymphocyte-associated protein-4; PD-1, programmed cell death protein 1; TNF-α, tumor necrosis factor α; IL-17, interleukin-17.