TY - JOUR
T1 - Identification of Deleterious NOTCH Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC
AU - Zhang, Kai
AU - Hong, Xiaohua
AU - Song, Zhengbo
AU - Xu, Yu
AU - Li, Chengcheng
AU - Wang, Guoqiang
AU - Zhang, Yuzi
AU - Zhao, Xiaochen
AU - Zhao, Zhengyi
AU - Zhao, Jing
AU - Huang, Mengli
AU - Huang, Depei
AU - Qi, Chuang
AU - Gao, Chan
AU - Cai, Shangli
AU - Gu, Feifei
AU - Hu, Yue
AU - Xu, Chunwei
AU - Wang, Wenxian
AU - Lou, Zhenkun
AU - Zhang, Yong
AU - Liu, Li
N1 - Funding Information:
This work was supported by the National Key Research and Development Program of China (2016YFC1303800) and National Natural Science Foundation of China (81773056).
Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2020/7/15
Y1 - 2020/7/15
N2 - Purpose: 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. Experimental Design: 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-NOTCHmut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. Results: Our 3DMed cohort (n ¼ 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n ¼ 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALKWT population, including objective response rate (2.20-fold, P ¼ 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46–0.81; P ¼ 0.001], and overall survival (HR, 0.56; 95% CI, 0.32–0.96; P ¼ 0.035). 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. Del-NOTCHmut 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-NOTCHmut. Conclusions: This work distinguishes del-NOTCHmut 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.
AB - Purpose: 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. Experimental Design: 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-NOTCHmut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. Results: Our 3DMed cohort (n ¼ 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n ¼ 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALKWT population, including objective response rate (2.20-fold, P ¼ 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46–0.81; P ¼ 0.001], and overall survival (HR, 0.56; 95% CI, 0.32–0.96; P ¼ 0.035). 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. Del-NOTCHmut 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-NOTCHmut. Conclusions: This work distinguishes del-NOTCHmut 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.
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U2 - 10.1158/1078-0432.CCR-19-3976
DO - 10.1158/1078-0432.CCR-19-3976
M3 - Article
C2 - 32241817
AN - SCOPUS:85088263065
SN - 1078-0432
VL - 26
SP - 3649
EP - 3661
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -