Targeting γδ T cells for the immunotherapy of endometrial cancer

Abstract Endometrial cancer (EC) is the most common gynecological neoplasm and the only gynecologic cancer with increasing incidence and mortality. EC is generally diagnosed at an early stage and is well managed with surgery and/or chemotherapy. However, EC patients with advanced/recurrent disease have a poor outcome and respond poorly to current treatments. Thus, there is the need to better investigate novel approaches. In this context, understanding the biology of the immune system is essential for recognition of new targets as well as optimization of existing immunotherapies. Growing evidences highlight an important role of both adaptive and innate immunity in generating a suppressive environment. However, little is known about the specific role of unconventional gamma delta (γδ) T cells. Therefore, the aim of this project is to characterize the frequency, phenotype and function of γδ T cells in EC. We used flow cytometry to characterize γδ T cells in peripheral blood (PB) and tumor tissue of EC patients and in PB of healthy donors and analyzed two public datasets of single cell RNA-sequencing to deepen the transcriptional profile of γδ T cells. These analyses revealed that the main subsets of γδ T cells, namely Vδ1 and Vδ2 T cells, infiltrate the tumor of EC patients. Moreover, they are characterized by the upregulation of immune checkpoints, such as PD-1. However, upon stimulation, they maintain their anti-tumor potential producing cytokines, e.g. IFN-γ and TNF-α. Overall, γδ T cells infiltrate EC and express immune checkpoints that can be targeted to implement the current immunotherapeutic strategies. Thus, further investigations are needed to exploit γδ T cells for EC therapy.