The regulation of CD73 in non-small cell lung cancer
Yumin Han1, Trevor Lee1, Yongfeng He1
1Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
Background:
Lung cancer is the leading cause of global cancer-related mortality. Although immune checkpoint therapy has achieved remarkable results in lung cancer, EGFR-mutant or ALK-positive non-smallcell lung cancer patients show limited benefit. Besides the low tumor mutational burden, PD-L1 expression and CD8+ tumor-infiltrating T cells, upregulation of CD73/adenosine pathway also contributes to the immune-inert microenvironment of EGFR-mutant NSCLC. However, the detailed mechanism underlying the regulation of CD73 is unclear.
Methods:
TCGA data was used to analyze the CD73 expression in cancer patients. Western blotting, qPCR, and ChIP-PCR were performed in multiple NSCLC cancer cell lines and patient derived organoids were used to explore the regulation of CD73 expression using western blotting.
Results:
CD73 expression was highly expressed in multiple cancer types. Pharmacological or genetic inhibition of EGFR, MEK, KRAS, or ALK dramatically reduced the CD73 mRNA and protein expression in NSCLC cancer cells and patient-derived organoids with EGFR mutation, KRAS mutation or ALK-rearrangement. C-Jun overexpression-induced CD73 mRNA and protein expression. ChIP assay showed that c-Jun bind to CD73 genomic regions.
Conclusions:
Higher CD73 expression in NSCLC cancer cells and patient-derived organoids with EGFR mutation, KRAS mutation or ALK-rearrangement. Mechanistically, CD73 is regulated by ERK-Jun pathway, wherein c-Jun regulates CD73 expression via binding to CD73 genomic regions.
Insights
The study reveals that the ERK-Jun pathway regulates CD73 expression in non-small cell lung cancer (NSCLC) with EGFR, KRAS, or ALK alterations. This finding is crucial for understanding immune evasion in NSCLC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Lung cancer is a leading cause of cancer mortality globally.
- Immune checkpoint therapy shows limited efficacy in EGFR-mutant or ALK-positive non-small cell lung cancer (NSCLC).
- The CD73/adenosine pathway contributes to an immune-inert microenvironment in EGFR-mutant NSCLC, but its regulation is unclear.
Purpose of the Study:
- To investigate the regulatory mechanisms of CD73 expression in NSCLC.
- To explore the role of CD73 in the context of specific driver mutations like EGFR, KRAS, and ALK.
Main Methods:
- Analysis of TCGA data for CD73 expression in cancer patients.
- Western blotting, qPCR, and ChIP-PCR in NSCLC cell lines and patient-derived organoids.
- Investigated the effect of inhibiting EGFR, MEK, KRAS, or ALK on CD73 expression.
Main Results:
- CD73 is highly expressed across multiple cancer types.
- Inhibition of EGFR, MEK, KRAS, or ALK significantly reduced CD73 mRNA and protein levels in NSCLC cells and organoids with relevant mutations.
- C-Jun overexpression led to increased CD73 expression, and ChIP assays confirmed c-Jun binding to CD73 genomic regions.
Conclusions:
- CD73 expression is elevated in NSCLC with EGFR, KRAS, or ALK alterations.
- The ERK-Jun pathway, specifically c-Jun binding to genomic regions, mechanistically regulates CD73 expression.
- Understanding this pathway offers potential therapeutic targets for overcoming immune resistance in NSCLC.
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