Research ArticleCancer

Characterization of ascites- and tumor-infiltrating γδ T cells reveals distinct repertoires and a beneficial role in ovarian cancer

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Science Translational Medicine  20 Jan 2021:
Vol. 13, Issue 577, eabb0192
DOI: 10.1126/scitranslmed.abb0192

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An innate response to ovarian cancer

Favorable outcomes for patients with epithelial ovarian cancer have been associated with infiltration of immune cells into tumors. In this study, Foord et al. investigated the contribution of a subset of immune cells, γδ T cells, to clinical outcomes in these patients. The authors demonstrated that tumor-infiltrating γδ T cells isolated from patients with ovarian cancer have distinct T cell receptors and exhibit more innate-like functions compared to blood- or ascites-derived γδ T cells. Furthermore, γδ T cell infiltration into tumors was associated with increased survival in patients with ovarian cancer. These findings suggest that promoting γδ T cell responses may be a therapeutic option for ovarian cancer.

Abstract

The role of γδ T cells in antitumor immunity has been under investigation for the past two decades, but little is known about their contribution to clinical outcomes in patients. Here, we set out to define the clonotypic, phenotypic, and functional features of γδ T cells in peripheral blood, ascites, and metastatic tumor tissue from patients with advanced epithelial ovarian cancer. T cell receptor (TCR) sequencing of the γ chain revealed that tumor-infiltrating γδ T cells have a unique and skewed repertoire with high TCR diversity and low clonality. In contrast, ascites-derived γδ T cells presented a lower TCR diversity and higher clonality, suggesting a TCR-dependent clonal focusing at this site. Further investigation showed that tumor samples had abundant γδ T cells with a tissue-resident, activation-associated phenotype, less usage of Vγ9 and an impaired response to adaptive-associated stimuli, implying an innate-like activation pathway, rather than an adaptive TCR-engaging pathway, at these tumor sites. Furthermore, high γδ T cell cytokine responsiveness upon stimulation was associated with a favorable outcome for patients in terms of both overall survival and reduced residual tumor burden after primary surgery. Last, the functionality of γδ T cells and patient survival were negatively affected by the proportions of CD39-expressing T cells, highlighting the potential of CD39 as a target to improve γδ T cell responses and unleash their antitumor capabilities.

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