Single-cell analysis of CD8+ T-cells by sex in renal cell carcinoma.

Abstract

e16501 Background: Although sex bias has been reported in the development and progression of renal cell carcinoma (RCC), the underlying mechanisms remain enigmatic. Here, we investigated the sex differences in the tumor microenvironment (TME) of RCC patients and explored a promising combination drug regimen to enhance the efficacy of immunotherapy. Methods: Single-cell RNA sequencing (scRNA-seq) data from four published datasets were analyzed to investigate the sex differences in RCC patients, and tumor tissues were collected to validate the sex differences using multiplex immunofluorescence (MxIF) and flow cytometry (FCM). The function of the androgen-androgen receptor axis in sex differences was explored in vivo and in vitro experiments. Results: By analyzing the scRNA-seq data of 220,156 cells and MxIF and FCM assays, we found that CD8+ T-cells infiltrated highly in the TME of male RCC, but mainly presented an exhausted and dysfunctional state. In vitro and in vivo experiments indicated that the dysfunction and exhaustion of CD8+ T-cells in male TME were induced by androgen. Clinically, higher serum androgen was significantly associated with a worse prognosis in male RCC patients receiving immunotherapy. Androgen receptor inhibitors could activate tumor-infiltrating CD8+ T-cells and enhance the efficacy of immunotherapy of RCC in vivo. Conclusions: We delineated the difference in TME between male and female patients with RCC, and demonstrated that the androgen-androgen receptor axis plays an important role in immunosuppression in male RCC. Clinically, androgen receptor inhibitors plus immunotherapy can be a promising combination regimen in RCC patients.