Abstract
NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non-small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy. Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCH mut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALK WT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46-0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32-0.96; P = 0.035). Del-NOTCH mut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCH mut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCH mut. This work distinguishes del-NOTCH mut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.
Highlights
Immune checkpoint inhibitors (ICI) have renovated the standard treatment for patients with non–small cell lung cancer (NSCLC), by virtue of the unprecedented prolongation of life [1,2,3]
Del-NOTCHmut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation
The data for the four independent cohorts were retrieved from published articles. [1] The Rizvi cohort contains 240 patients with advanced NSCLC treated with anti–PD-1/programmed death ligand 1 (PD-L1) monotherapy or combination therapy with anti–CTLA-4, and their tumor tissues were profiled with MSK-IMPACT panel (341-gene panel, 0.98 Mb, 56 patients; 410-gene panel, 1.06 Mb, 164 patients; 468-gene panel, 1.22 Mb, 20 patients; ref. 29)
Summary
Immune checkpoint inhibitors (ICI) have renovated the standard treatment for patients with non–small cell lung cancer (NSCLC), by virtue of the unprecedented prolongation of life [1,2,3]. Durable response of ICIs merely occurs in a tiny minority, which. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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