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

Abstract

<div>Abstract<p>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<sup>+</sup> 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.</p>Significance:<p>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.</p></div>

Development of a novel copper metabolism-related risk model to predict prognosis and tumor microenvironment of patients with stomach adenocarcinoma

“…A nomogram was then created to facilitate clinical application, incorporating clinical features to provide a customized scoring system for physicians. A previous study showed that copper regulates key signaling pathways that underlie PD-L1-mediated immune evasion in cancer; reducing copper levels in tumor cells with copper chelators increases CD8 + T cells and inhibits cancer progression (Voli et al, 2020). Thus, we hypothesized that copper metabolism shuts down antitumor immunity.…”

“…(Kim et al, 2008). Recently, copper has been shown to regulate the expression of programmed death ligand 1 (PDL1), a transmembrane protein regulated on the surface of some cancer cells that allows immune evasion (Voli et al, 2020). Furthermore, the anti-tumor effects of the immune response depend on effective mitochondrial function, and copper deficiency inhibits the immune response (Shanbhag et al, 2021).…”

The role of metal ions in the occurrence, progression, drug resistance, and biological characteristics of gastric cancer

“…Additionally, copper impacts PD-L1, an immune checkpoint inhibitor implicated in cancer immune evasion. Studies have highlighted that depleting copper facilitates the degradation of PD-L1, inhibiting tumor growth and enhancing survival rates in animal models (Voli et al, 2020).…”

Cuproptosis-related molecular subtypes direct T cell exhaustion phenotypes and therapeutic strategies for patients with lung adenocarcinoma

“…Similarly, artificially overexpressing copper importer SLC31A1 resulted in Cu over-accumulation, thereby triggered cuproptosis in A549 lung cancer cells (Tsvetkov et al, 2022). Whereas, depleting cupric ion with copper chelators reduced PD-L1 expression by both inhibiting PD-L1 transcription and promoting PD-L1 ubiquitination degradation in xenograft mouse (Voli et al, 2020). The evidence suggested that cuproptosis was tightly associated with tumor progression.…”