Impact of ER stress on gd T cells in tumor microenvironment

Gamma delta T cells are unconventional T lymphocytes that share features of the innate and the adaptive immune systems. They are found enriched in epithelial and mucosal tissues, where they can recognize tissue stress and cancer cells. Their function is to limit the dissemination of infected and malignant cells and to maintain tissue integrity. Gamma delta T cells exert cytotoxicity against a wide range of solid and hematological tumors, and they are the most significant favorable prognostic factor clinically across 39 cancer types. Therefore, gamma delta T cells constitute a potential immunotherapeutic to promote anti-cancer response. However, the tumor microenvironment can impair their cytotoxic function, which might permit tumor growth. The mechanisms by which these T cells are rendered dysfunctional are not yet fully understood. Endoplasmic reticulum stress (ER stress) within the tumor microenvironment can impair the anti-tumor function of local immune cells and has been identified as one mechanism that favors tumor growth. However, despite their therapeutic relevance, the impact of ER stress on gamma delta T cells has not been studied. Here, we will for the first time elucidate how ER stress within the tumor microenvironment impacts the activation and anti-tumor activity of tissue resident gamma delta T cells. This study will give a new perspective for developing effective anti-tumor therapeutic approaches to harness local immunity.