Intra-tumoral copper modulates PD-L1 expression and influences tumor immune evasion

Therapeutic checkpoint antibodies blocking PD1/PD-L1 signaling have radically improved clinical outcomes in cancer. However, the regulation of PD-L1 expression on tumor cells is still poorly understood. Here we show that intra-tumoral copper levels influence PD-L1 expression in cancer cells. Deep analysis of the TCGA database and TMA showed strong correlation between the major copper influx transporter CTR-1 and PD-L1 expression across many cancers but not in corresponding normal tissues. Copper supplementation enhanced PD-L1 expression at mRNA and protein levels in cancer cells and RNAseq revealed that copper regulates key signaling pathways mediating PD-L1-driven cancer immune evasion. Conversely, copper chelators inhibited phosphorylation of STAT3 and EGFR and promoted ubiquitin-mediated degradation of PD-L1. Copper-chelating drugs also significantly increased the number of tumor-infiltrating CD8+T and natural-killer cells, slowed tumor growth, and improved mouse survival. Overall, this study reveals an important role for copper in regulating PD-L1 and suggests that anti-cancer immunotherapy might be enhanced by pharmacologically reducing intra-tumor copper levels.