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Open Access 01-12-2021 | NSCLC | Research article

Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy

Authors: Junyu Long, Dongxu Wang, Xu Yang, Anqiang Wang, Yu Lin, Mingjun Zheng, Haohai Zhang, Xinting Sang, Hanping Wang, Ke Hu, Haitao Zhao

Published in: BMC Medicine | Issue 1/2021

Abstract

Background

Immune checkpoint inhibitor (ICI) therapy elicits durable antitumor responses in patients with many types of cancer. Genomic mutations may be used to predict the clinical benefits of ICI therapy. NOTCH homolog-4 (NOTCH4) is frequently mutated in several cancer types, but its role in immunotherapy is still unclear. Our study is the first to study the association between NOTCH4 mutation and the response to ICI therapy.

Methods

We tested the predictive value of NOTCH4 mutation in the discovery cohort, which included non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, esophagogastric cancer, and bladder cancer patients, and validated it in the validation cohort, which included non-small cell lung cancer, melanoma, renal cell carcinoma, colorectal cancer, esophagogastric cancer, glioma, bladder cancer, head and neck cancer, cancer of unknown primary, and breast cancer patients. Then, the relationships between NOTCH4 mutation and intrinsic and extrinsic immune response mechanisms were studied with multiomics data.

Results

We collected an ICI-treated cohort (n = 662) and found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate (ORR: 42.9% vs 25.9%, P = 0.007), durable clinical benefit (DCB: 54.0% vs 38.1%, P = 0.021), progression-free survival (PFS, hazard ratio [HR] = 0.558, P < 0.001), and overall survival (OS, HR = 0.568, P = 0.006). In addition, we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort (n = 1423). Based on multiomics data, we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity, including a high tumor mutational burden, the expression of costimulatory molecules, and activation of the antigen-processing machinery, and NOTCH4 mutation positively correlates activated antitumor immunity, including infiltration of diverse immune cells and various immune marker sets.

Conclusions

Our findings indicated that NOTCH4 mutation serves as a novel biomarker correlated with a better response to ICI therapy.

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Title: Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy
Authors: Junyu Long
Dongxu Wang
Xu Yang
Anqiang Wang
Yu Lin
Mingjun Zheng
Haohai Zhang
Xinting Sang
Hanping Wang
Ke Hu
Haitao Zhao
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: NSCLC
NSCLC
Checkpoint Inhibitors
Biomarkers
Published in: BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-021-02031-3

At a glance: The STEP trials

Springer Medicine

Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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