Abstract：
:Therapeutic checkpoint antibodies blocking programmed death receptor 1/programmed death ligand 1 (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 intratumoral copper levels influence PD-L1 expression in cancer cells. Deep analysis of the The Cancer Genome Atlas database and tissue microarrays showed strong correlation between the major copper influx transporter copper transporter 1 (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 RNA sequencing 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 anticancer immunotherapy might be enhanced by pharmacologically reducing intratumor copper levels. SIGNIFICANCE: These findings characterize the role of copper in modulating PD-L1 expression and contributing to cancer immune evasion, highlighting the potential for repurposing copper chelators as enhancers of antitumor immunity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/19/4129/F1.large.jpg.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Voli F,Valli E,Lerra L,Kimpton K,Saletta F,Giorgi FM,Mercatelli D,Rouaen JRC,Shen S,Murray JE,Ahmed-Cox A,Cirillo G,Mayoh C,Beavis PA,Haber M,Trapani JA,Kavallaris M,Vittorio Odoi
10.1158/0008-5472.CAN-20-0471subject
Has Abstractpub_date
2020-10-01 00:00:00pages
4129-4144issue
19eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-20-0471journal_volume
80pub_type
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