Abstract
Immune checkpoints blockades have shown promising clinical effects in various malignancies, but the overall response rate is low. Here, the immune features are comprehensively characterized in >10 000 cancer patients from The Cancer Genome Atlas and significantly positive correlations are observed between targets of Sunitinib and inhibitory immune checkpoints and suppressive immune cells. It is further confirmed that Sunitinib treatment increases the antitumor immunity in a phase III trial. Mechanistically, it is discovered that Sunitinib regulates the stability of tumor PD-L1 via p62, that p62 can bind to PD-L1 and specifically promote its translocation into autophagic lysosome for degradation. Preclinically, Sunitinib shows a synergistic antitumor effect with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody (mAb) in melanoma and nonsmall cell lung cancer (NSCLC) immune competent mice by promoting the tumor-infiltrating lymphocytes activity. Clinically, a higher PD-L1 level but a lower p62 level in the tumor region of responders as compared to those of nonresponders among anti-PD-1-treated NSCLC patients is observed. Taken together, by utilizing rigorous computational analysis, functional characterization in vitro and in vivo, and neoadjuvent clinical trial, a novel molecular mechanism is revealed regarding the regulation of PD-L1 via p62, thus providing a novel therapeutic strategy by the combination treatment of CTLA-4 with Sunitinib.