This study reveals that CRTC1 promotes PD-L1 expression through activation of the Notch1/Akt signaling pathway in non-small cell lung cancer (NSCLC), thereby suppressing T-cell function and reducing immunotherapy efficacy. It also demonstrates that CRTC1 knockdown significantly enhances the therapeutic effects of anti-PD-L1 treatment, providing a novel target for overcoming immune therapy resistance mechanisms.
Literature Overview
The article 'CRTC1 enhances PD-L1-mediated tumor immunosuppression in non-small cell lung cancer via the Notch1/Akt signaling pathway', published in *Frontiers in Immunology*, reviews the role of CRTC1 in NSCLC immune escape and its relationship with PD-L1 and the Notch1/Akt signaling pathway. Through cell models, mouse xenograft models, and multiple molecular biology experiments, the study uncovers how CRTC1 promotes tumor cell proliferation, migration, and immune escape while inhibiting T-cell function. The section concludes with
Background Knowledge
Non-small cell lung cancer (NSCLC), the major lung cancer subtype accounting for ~85% of cases, has a five-year survival rate below 20%. Although PD-L1 immune checkpoint inhibitors like atezolizumab are approved for advanced NSCLC, only 20-30% of patients respond, with resistance and toxicity limiting efficacy. Immune escape mechanisms in the tumor microenvironment are complex, with dynamic PD-L1 regulation influenced by multiple signaling pathways, particularly the Notch1/Akt axis, which plays a critical role in tumor progression. Researchers focused on the CRTC family, known for metabolic and transcriptional regulation, but its role in NSCLC immunotherapy remains unexplored. This study first demonstrates CRTC1's interaction with Notch1 in NSCLC, activating Akt signaling to enhance PD-L1 expression, suppress T-cell function, and weaken anti-PD-L1 therapy. This mechanism provides a new target for immune therapy resistance and theoretical foundation for combination treatments.
Research Methods and Experiments
The study employed A549 and NCI-H1299 cell lines alongside mouse Lewis lung carcinoma (LLC) cells for CRTC1 overexpression and knockdown experiments to evaluate impacts on cell proliferation, migration, invasion, and apoptosis. Co-cultures of LLC cells with CTLL-2 T cells were used to analyze T-cell functional changes. In C57BL/6J mouse models combined with atezolizumab treatment, the effects of CRTC1 modulation on PD-L1 immunotherapy were assessed. Protein interactions were validated via Co-IP, signaling pathways analyzed using Western blot, qPCR, and ELISA, while PD-L1 expression, CXCL10/CXCL11 secretion, and T-cell cytotoxicity were measured through LDH release assays.
Key Conclusions and Perspectives
Research Significance and Prospects
This study identifies CRTC1 as a critical player in NSCLC immune escape, suggesting its potential as both a biomarker for PD-L1 therapy resistance and a therapeutic target. Future research could explore small-molecule inhibitors or gene-based interventions targeting CRTC1 combined with PD-L1 blockade to overcome resistance and enhance anti-tumor immunity. Additionally, the findings highlight the Notch1/Akt pathway's role in immune suppression, offering new directions for combination immunotherapy strategies in NSCLC.
Conclusion
This study systematically demonstrates that CRTC1 enhances PD-L1 expression through the Notch1/Akt pathway in non-small cell lung cancer (NSCLC), suppressing T-cell-mediated immune surveillance. The researchers confirmed in multiple cell and animal models that CRTC1 expression levels strongly correlate with PD-L1 upregulation and T-cell dysfunction, with CRTC1 overexpression diminishing PD-L1 blockade efficacy. Further experiments showed that CRTC1 knockdown significantly improves atezolizumab's anti-tumor activity, enhancing T-cell infiltration and cytokine secretion. These findings uncover a novel mechanism of immune therapy resistance in NSCLC while identifying potential combination therapy targets. Future research should focus on developing specific CRTC1 or Notch1/Akt inhibitors to improve clinical response rates and enhance immunotherapy outcomes for NSCLC patients.
