MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer
A Bouillez1, H Rajabi1, C Jin1
1Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Abstract:
Immunotherapeutic approaches, particularly programmed death 1/programmed death ligand 1 (PD-1/PD-L1) blockade, have improved the treatment of non-small-cell lung cancer (NSCLC), supporting the premise that evasion of immune destruction is of importance for NSCLC progression. However, the signals responsible for upregulation of PD-L1 in NSCLC cells and whether they are integrated with the regulation of other immune-related genes are not known. Mucin 1 (MUC1) is aberrantly overexpressed in NSCLC, activates the nuclear factor-κB (NF-κB) p65→︀ZEB1 pathway and confers a poor prognosis. The present studies demonstrate that MUC1-C activates PD-L1 expression in NSCLC cells. We show that MUC1-C increases NF-κB p65 occupancy on the CD274/PD-L1 promoter and thereby drives CD274 transcription. Moreover, we demonstrate that MUC1-C-induced activation of NF-κB→︀ZEB1 signaling represses the TLR9 (toll-like receptor 9), IFNG, MCP-1 (monocyte chemoattractant protein-1) and GM-CSF genes, and that this signature is associated with decreases in overall survival. In concert with these results, targeting MUC1-C in NSCLC tumors suppresses PD-L1 and induces these effectors of innate and adaptive immunity. These findings support a previously unrecognized central role for MUC1-C in integrating PD-L1 activation with suppression of immune effectors and poor clinical outcome.
Insights
Mucin 1 (MUC1) drives programmed death-ligand 1 (PD-L1) expression in non-small-cell lung cancer (NSCLC), suppressing anti-tumor immunity. Targeting MUC1-C may restore immune responses and improve NSCLC outcomes.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immunotherapy, including PD-1/PD-L1 blockade, has advanced non-small-cell lung cancer (NSCLC) treatment.
- Understanding PD-L1 upregulation signals in NSCLC and their link to other immune genes is crucial.
- Aberrant Mucin 1 (MUC1) expression in NSCLC activates NF-κB signaling and correlates with poor prognosis.
Purpose of the Study:
- To investigate the role of MUC1-C in regulating PD-L1 expression in NSCLC cells.
- To determine if MUC1-C integrates PD-L1 regulation with other immune-related genes.
- To explore the therapeutic potential of targeting MUC1-C in NSCLC.
Main Methods:
- Assessed MUC1-C's effect on PD-L1 expression in NSCLC cells.
- Analyzed NF-κB p65 binding to the CD274/PD-L1 promoter.
- Investigated MUC1-C-induced changes in the expression of TLR9, IFNG, MCP-1, and GM-CSF.
- Evaluated the impact of targeting MUC1-C on PD-L1 and immune gene expression in NSCLC tumors.
Main Results:
- MUC1-C was found to activate PD-L1 expression in NSCLC cells.
- MUC1-C increases NF-κB p65 binding to the CD274/PD-L1 promoter, driving PD-L1 transcription.
- MUC1-C-mediated NF-κB→ZEB1 signaling represses immune genes (TLR9, IFNG, MCP-1, GM-CSF), correlating with decreased survival.
- Targeting MUC1-C in NSCLC tumors suppressed PD-L1 and upregulated these immune effectors.
Conclusions:
- MUC1-C plays a central role in activating PD-L1 expression in NSCLC.
- MUC1-C integrates PD-L1 upregulation with the suppression of key innate and adaptive immune genes.
- Targeting MUC1-C represents a promising strategy for enhancing anti-tumor immunity in NSCLC.
