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.
Highlights
Lung cancer, histologically differentiated into small cell lung cancer and non–small cell lung cancer, ranks among the most common cause of cancer-related death worldwide
Tumor mutation burden (TMB), PDL1 expression, tumor immune microenvironment (TIME), and some specific gene mutations have been reported to be associated with Immune checkpoint inhibitors (ICIs) response [5–9], only a few of them have been validated in the clinic and even those validated biomarkers still had their limitations
The frequency of AHNAK nucleoprotein 2 (AHNAK2) mutation was up to 11%, indicating that it was not a rare mutation in non-small cell lung cancer (NSCLC)
Summary
Histologically differentiated into small cell lung cancer and non–small cell lung cancer, ranks among the most common cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85% of total cases routinely being treated with surgery, chemotherapy, radiation therapy, or targeted therapy. Tumor immune checkpoint inhibitors (ICIs), including programmed death receptor 1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized NSCLC treatment [1, 2]. Predictive biomarkers of ICI treatment response are required to provide effective therapy. Tumor mutation burden (TMB), PDL1 expression, tumor immune microenvironment (TIME), and some specific gene mutations have been reported to be associated with ICI response [5–9], only a few of them have been validated in the clinic and even those validated biomarkers still had their limitations
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