Deleterious AHNAK2 Mutation as a Novel Biomarker for Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer
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Yanan Cui1, Xinyin Liu1, Yuemin Wu1
1Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Abstract:
Immune checkpoint inhibitors (ICIs) have exhibited promising efficacy in non-small cell lung cancer (NSCLC), but the response occurs in only a minority of patients. In clinic, biomarkers such as TMB (tumor mutation burden) and PD-L1 (programmed cell death 1 ligand 1) still have their limitations in predicting the prognosis of ICI treatment. Hence, reliable predictive markers for ICIs are urgently needed. A public immunotherapy dataset with clinical information and mutational data of 75 NSCLC patients was obtained from cBioPortal as the discovery cohort, and another immunotherapy dataset of 249 patients across multiple cancer types was collected as the validation. Integrated bioinformatics analysis was performed to explore the potential mechanism, and immunohistochemistry studies were used to verify it. AHNAK nucleoprotein 2 (AHNAK2) was reported to have pro-tumor growth effects across multiple cancers, while its role in tumor immunity was unclear. We found that approximately 11% of the NSCLC patients harbored AHNAK2 mutations, which were associated with promising outcomes to ICI treatments (ORR, p = 0.013). We further found that AHNAK2 deleterious mutation (del-AHNAK2 mut) possessed better predictive function in NSCLC than non-deleterious AHNAK2 mutation (PFS, OS, log-rank p < 0.05), potentially associated with stronger tumor immunogenicity and an activated immune microenvironment. This work identified del-AHNAK2 mut as a novel biomarker to predict favorable ICI response in NSCLC.
Insights
Deleterious mutations in AHNAK2 predict a better response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). This finding offers a novel biomarker for predicting favorable ICI treatment outcomes in NSCLC patients.
Area of Science:
- Oncology
- Immunotherapy
- Genetics
Background:
- Immune checkpoint inhibitors (ICIs) show promise in non-small cell lung cancer (NSCLC), but patient response is limited.
- Current biomarkers like tumor mutation burden (TMB) and programmed cell death 1 ligand 1 (PD-L1) have predictive limitations.
- Reliable biomarkers are needed to predict ICI treatment efficacy in NSCLC.
Purpose of the Study:
- To identify novel biomarkers for predicting response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC).
- To investigate the role of AHNAK nucleoprotein 2 (AHNAK2) in tumor immunity and its potential as a predictive marker for ICI therapy.
Main Methods:
- Utilized public immunotherapy datasets for NSCLC (n=75) and multiple cancer types (n=249) for discovery and validation.
- Performed integrated bioinformatics analysis to explore potential mechanisms.
- Conducted immunohistochemistry studies for verification.
Main Results:
- AHNAK2 mutations were found in approximately 11% of NSCLC patients and were associated with favorable ICI treatment outcomes (Objective Response Rate, p = 0.013).
- Deleterious AHNAK2 mutations (del-AHNAK2mut) demonstrated superior predictive value for progression-free survival (PFS) and overall survival (OS) compared to non-deleterious mutations (log-rank p < 0.05).
- del-AHNAK2mut was linked to enhanced tumor immunogenicity and an activated immune microenvironment.
Conclusions:
- AHNAK2 mutations, particularly deleterious ones, serve as a novel predictive biomarker for favorable response to ICIs in NSCLC.
- del-AHNAK2mut may indicate a stronger tumor immune response, contributing to better ICI efficacy.
- This discovery addresses the urgent need for reliable predictive markers in NSCLC immunotherapy.
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