Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer
Nitin Roper1, Moises J Velez2, Alberto Chiappori3
1Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
Abstract:
Immune checkpoint blockade (ICB) benefits only a small subset of patients with small cell lung cancer (SCLC), yet the mechanisms driving benefit are poorly understood. To identify predictors of clinical benefit to ICB, we performed immunogenomic profiling of tumor samples from patients with relapsed SCLC. Tumors of patients who derive clinical benefit from ICB exhibit cytotoxic T-cell infiltration, high expression of antigen processing and presentation machinery (APM) genes, and low neuroendocrine (NE) differentiation. However, elevated Notch signaling, which positively correlates with low NE differentiation, most significantly predicts clinical benefit to ICB. Activation of Notch signaling in a NE human SCLC cell line induces a low NE phenotype, marked by increased expression of APM genes, demonstrating a mechanistic link between Notch activation, low NE differentiation and increased intrinsic tumor immunity. Our findings suggest Notch signaling as a determinant of response to ICB in SCLC.
Insights
Notch signaling predicts response to immune checkpoint blockade (ICB) in small cell lung cancer (SCLC). Activating Notch signaling enhances tumor immunity, suggesting it as a key determinant for ICB treatment success in SCLC patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint blockade (ICB) efficacy is limited in small cell lung cancer (SCLC).
- Mechanisms predicting ICB response in SCLC remain largely unknown.
- Understanding these mechanisms is crucial for improving SCLC treatment outcomes.
Purpose of the Study:
- Identify biomarkers predicting clinical benefit to ICB in relapsed SCLC.
- Investigate the role of Notch signaling in SCLC response to ICB.
- Elucidate the link between Notch signaling, neuroendocrine differentiation, and tumor immunity.
Main Methods:
- Immunogenomic profiling of tumor samples from SCLC patients.
- Correlation analysis of gene expression with clinical response to ICB.
- Functional studies involving Notch signaling activation in SCLC cell lines.
Main Results:
- Clinical benefit from ICB in SCLC correlates with cytotoxic T-cell infiltration, high antigen processing machinery (APM) gene expression, and low neuroendocrine (NE) differentiation.
- Elevated Notch signaling is the strongest predictor of ICB clinical benefit.
- Notch activation in SCLC cells reduces NE differentiation and increases APM gene expression, enhancing intrinsic tumor immunity.
Conclusions:
- Notch signaling is a significant determinant of response to ICB in SCLC.
- Targeting Notch signaling may enhance ICB efficacy in SCLC.
- Findings provide a mechanistic basis for predicting and potentially improving ICB response in SCLC.
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