γδ T Cells: Unexpected Regulators of Cancer Development and Progression

Abstract

Accumulating evidence suggests a role for gamma delta (γδ) T cells as unexpected drivers of tumor development and progression. These protumoral γδ T cells are abundant in the tumor microenvironment in both mouse and human. They promote tumor progression by: (i) inducing an immunosuppressive tumor microenvironment and angiogenesis via cytokine production; (ii) functioning as regulatory T (Treg)/T helper 2 (Th2)-like cells; (iii) interfering with dendritic cell (DC) effector function; and (iv) inhibiting antitumor adaptive T cell immunity via the programmed death-1 (PD-1)-programmed death ligand-1 (PD-L1) pathway. Understanding how these cells are regulated and what their specific role in cancer is will provide insight for the development of approaches that specifically target these cells and can thereby improve the efficacy of cancer immunotherapies.

Keywords: PD-1 regulation; protumoral; tumor microenvironment; γδ T cells.

Figure 1. γδT cells in cancer

γδT cells in cancer can be regulated through cytokines, microbiota, and PAMP engagement for expansion and differentiation within the tumor microenvironment. These pro-tumor γδT cells promote tumor progression and metastasis via induction of immunosuppression and angiogenesis by cytokine secretion, mimicking Treg/Th2-like activity, interfering with DC effector function, and directly inhibiting antitumor adaptive T cell immunity. MDSC, myeloid-derived suppressor cells; PAMP, pathogen-associated molecular patterns, PD-1, program death-1; PD-L1, program death ligand-1; TAM, tumor-associated macrophages; TGF-β, transforming growth factor β; TLR, toll-like receptor; Treg, regulatory T cells.