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Figure S1 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion

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posted on 2023-03-31, 03:47 authored by Florida Voli, Emanuele Valli, Luigi Lerra, Kathleen Kimpton, Federica Saletta, Federico M. Giorgi, Daniele Mercatelli, Jourdin R.C. Rouaen, Sylvie Shen, Jayne E. Murray, Aria Ahmed-Cox, Giuseppe Cirillo, Chelsea Mayoh, Paul A. Beavis, Michelle Haber, Joseph A. Trapani, Maria Kavallaris, Orazio Vittorio

Co-expression plots of VST-normalized gene expression profiles derived from TCGA datasets for PD-L1 and four copper-responsive genes

Funding

NHMRC

Cure Cancer Australia

Cancer Institute NSW

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology

Australian Research Council

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Cancer Institute New South Wales

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ARTICLE 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. 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.

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    Cancer Research

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    Keywords

    Drug TargetsHematological CancersImmunotherapyCheckpoint blockadePediatric Cancers

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