ImmunoTargets and Therapy (Dec 2023)

NOTCH1 Mutations Predict Superior Outcomes of Immune Checkpoint Blockade in Non-Small Cell Lung Cancer

  • Huang Q,
  • Cao H,
  • Yao Q,
  • Zhou X,
  • Li H,
  • Bai Q,
  • Hu H

Journal volume & issue
Vol. Volume 12
pp. 165 – 173

Abstract

Read online

Qingyuan Huang,1– 3,* Hang Cao,1– 3,* Qianlan Yao,3– 5,* Xiaoyan Zhou,3– 5 Hang Li,1– 3 Qianming Bai,3– 5 Hong Hu1– 3 1Departments of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China; 2Institute of Thoracic Oncology, Fudan University, Shanghai, 200032, People’s Republic of China; 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China; 4Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China; 5Institute of Pathology, Fudan University, Shanghai, 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong Hu; Qianming Bai, Email [email protected]; [email protected]: NOTCH1 is frequently mutated in non-small cell lung cancer (NSCLC), and also is a poor therapeutic target. It is of clinical importance to investigate the effects of NOTCH1 mutations on anti-tumor immunity and response to immune checkpoint blockade (ICB).Methods: An observational study with targeted sequencing in 963 NSCLC patients at our center were performed (FUSCC cohort). Data of the Cancer Genome Atlas Pan-Lung Cancer study (TCGA cohort) were analyzed, and gene set enrichment analysis (GSEA) was performed. The Samstein et al cohort included 350 patients with advanced NSCLC undergoing genomic profiling with the MSK-IMPACT assay, and receiving at least one dose of ICB therapy.Results: NOTCH1 mutations were more common in smokers and patients with squamous-cell carcinoma (SCC) (all P value < 0.05). For patients who did not receive ICB therapy (TCGA cohort), the overall survival (OS) of NOTCH1-mutant and -WT patients were comparable (log-rank P = 0.72), while for patients who received ICB therapy in the Samstein et al cohort, NOTCH1-mutant patients had significantly superior OS than WT patients (log-rank P = 0.041). On multivariate Cox analysis, the predictive value of NOTCH1 mutations reached marginal statistical significance (HR, 0.42; 95% CI, 0.17– 1.04; P = 0.059). The median of TMB for NOTCH1-mutant tumors was significantly higher than that for NOTCH1-WT tumors, and GSEA revealed that NOTCH1 mutations manifested various defects in the repair of DNA damage. NOTCH1-mutant tumors displayed an inflamed tumor microenvironment (TME), manifesting as increased PD-L1 expression and tumor-infiltrating CD8+ T cells.Conclusion: NOTCH1 mutations define a molecular subtype of NSCLC, which are more common in smokers and patients with SCC, are characterized with higher TMB, inflamed TME, and display improved survival of ICB therapy for NSCLC patients.Keywords: NOTCH1, non-small cell lung cancer, immunotherapy, survival, tumor mutational burden, tumor microenvironment

Keywords