γδ T cells and cancer
Lukas Bolini, Seth B. Coffelt, Bruno Silva-Santos, David L. Wiest, Lorenzo Galluzzi
Lukas Bolini, Seth B. Coffelt, Bruno Silva-Santos, David L. Wiest, Lorenzo Galluzzi
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Review

γδ T cells and cancer

Abstract

γδ T cells are a subset of lymphoid cells that, unlike their αβ lineage counterparts, express a heterodimeric TCR that mostly operates in an MHC-independent manner. γδ T cells are abundant in barrier tissues, where they continuously monitor epithelial cells for signs of stress or damage. Thus, γδ T cells are among the first responders to pathophysiological conditions, including viral infection and oncogenesis. Human γδ T cells can be classified based on TCR γ and δ chain usage into three main subsets: (a) Vγ9+Vδ2+ cells, accounting for most circulating γδ T cells; (b) Vδ1+ cells, which are common in epithelial linings, and (c) Vδ3+ T cells, which are fairly rare but exhibit unique specificities. Moreover, both human and murine γδ T cells can assume a spectrum of states with divergent phenotypic and functional properties. Accumulating evidence demonstrates that γδ T cells can mediate robust anticancer effects or support tumor progression and resistance to therapy, depending on numerous variables, including functional state and tumor type. Here, we critically discuss the context-dependent interaction between γδ T cells and cancer, focusing on recent developments and the challenges facing current efforts to manipulate this versatile lymphocyte subset for therapeutic purposes.

Authors

Lukas Bolini, Seth B. Coffelt, Bruno Silva-Santos, David L. Wiest, Lorenzo Galluzzi

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Figure 2

Context-dependent impact of γδ T cells on tumor progression and response to therapy.

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Context-dependent impact of γδ T cells on tumor progression and response...
γδ T cells exist across a spectrum of phenotypic and functional phenotypes, hence impacting tumor progression and response to therapy in a highly context-dependent manner. (A) So-called γδT1 effectors, which require EOMES and T-bet transcription factors and are characterized by CD27 and IFN-γ coexpression, generally exert potent anticancer activity. This reflects not only the potent antineoplastic effects of IFN-γ itself, but also the ability of γδT1 cells to secrete cytotoxic effectors, including PRF1 and GZMB, and to engage death receptors on the surface of malignant cells. (B) Conversely, γδT17 effectors, which require MAF and RORγt transcriptional activity, lack CD27 but express CCR6 and IL17A, most often promoting cancer progression and resistance to therapy. Such an effect largely emerges from the ability of γδT17 cells to polarize the tumor microenvironment (TME) toward an immunosuppressed state dominated by CSFR1+ and/or CX3CR1+ tumor-associated macrophages (TAMs), KIT+ tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs).