Targeting YAP1-CD70 axis potentiates the efficacy of anti-PD-1 therapy in prostate cancer

The mechanisms by which prostate cancer (PCa) evades anti-tumor immunity and the immune checkpoint blockade (ICB) response are poorly understood. Yes-associated protein 1 (YAP1) activation is a common feature in PCa. However, to date, there is no direct evidence regarding the effect of YAP1 activity on anti-tumor immunity in PCa patients. In this study, we discovered that YAP1 expression is usually abundant in PCa tissues. Transcriptome analysis revealed that PD-L1 and the immune costimulatory molecule CD70 were consistently upregulated in YAP1-activated PCa cells. Meanwhile, CD70 is also abundantly exhibited in ICB non-responder patients, but absent in ICB responders, who usually show high cytotoxic T cell infiltration. More importantly, CD70 inhibition restores the sensitivity to anti-PD-1 immunotherapy in YAP1-activated PCa cells. Mechanistically, YAP1 directly regulates the transcription of CD70 through cooperation with DNA-binding factor RUNX1. The upregulation of CD70 thus suppresses immune cell infiltration into malignant lesions and promotes the exhaustion of CD8 + T cells to facilitate evasion from immunosurveillance. Taken together, our findings define the YAP1-CD70 signaling axis as a novel immunosuppressive mechanism in PCa, which provides new insights into the potential of targeting the CD70 pathway to help further subdivide the population of PCa patients who can benefit from immunotherapy.