Single‐cell transcriptomics identify TNFRSF1B as a novel T‐cell exhaustion marker for ovarian cancer

Abstract

Abstract Background: Ovarian cancer (OC) patients routinely show poor immunotherapeutic response due to the complex tumour microenvironment (TME). It is urgent to explore new immunotherapeutic markers. Methods: Through the single‐cell RNA sequencing (scRNA‐seq) analyses on high‐grade serous OC (HGSOC), moderate severity borderline tumour and matched normal ovary, we identified a novel exhausted T cells subpopulation that related to poor prognosis in OC. Histological staining, multiple immunofluorescences, and flow cytometry were applied to validate some results from scRNA‐seq. Furthermore, a tumour‐bearing mice model was constructed to investigate the effects of TNFRSF1B treatment on tumour growth in vivo. Results: Highly immunosuppressive TME in HGSOC is displayed compared to moderate severity borderline tumour and matched normal ovary. Subsequently, a novel exhausted subpopulation of CD8+TNFRSF1B+ T cells is identified, which is associated with poor survival. In vitro experiments demonstrate that TNFRSF1B is specifically upregulated on activated CD8+ T cells and suppressed interferon‐γ secretion. The expression of TNFRSF1B on CD8+T cells is closely related to OC clinical malignancy and is a marker of poor prognosis through 140 OC patients’ verification. In addition, the blockade of TNFRSF1B inhibits tumour growth via profoundly remodeling the immune microenvironment in the OC mouse model. Conclusions: Our transcriptomic results analyzed by scRNA‐seq delineate a high‐resolution snapshot of the entire tumour ecosystem of OC TME. The major applications of our findings were an exhausted subpopulation of CD8+TNFRSF1B+ T cells for predicting OC patient prognosis and the potential therapeutic value of TNFRSF1B. These findings demonstrated the clinical value of TNFRSF1B as a potential immunotherapy target and extended our understanding of factors contributing to immunotherapy failure in OC.

Keywords

• Ovarian cancer
• single‐cell RNA‐seq
• TNFRSF1B
• tumour microenvironment