TNF-Alpha Pathway Alternation Predicts Survival of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer.

Anqi Lin,Hongman Zhang,Ze Deng,Hui Meng,Jian Zhang,Peng Luo,Tianqi Gu

doi:10.3389/fimmu.2021.667875

Anqi Lin, Hongman Zhang + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2021.667875

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Abstract

Translational research on immune checkpoint inhibitors (ICIs) has been underway. However, in the unselected population, only a few patients benefit from ICIs. Therefore, screening predictive markers of ICI efficacy has become the current focus of attention. We collected mutation and clinical data from an ICI-treated non-small cell lung cancer (NSCLC) cohort. Then, a univariate Cox regression model was used to analyze the relationship between tumor necrosis factor α signaling mutated (TNFα-MT) and the prognosis of immunotherapy for NSCLC. We retrospectively collected 36 NSCLC patients (local-cohort) from the Zhujiang Hospital of Southern Medical University and performed whole-exome sequencing (WES). The expression and mutation data of The Cancer Genome Atlas (TCGA)-NSCLC cohort were used to explore the association between TNFα-MT and the immune microenvironment. A local cohort was used to validate the association between TNFα-MT and immunogenicity. TNFα-MT was associated with significantly prolonged overall survival (OS) in NSCLC patients after receiving immunotherapy. Additionally, TNFα-MT is related to high immunogenicity (tumor mutational burden, neoantigen load, and DNA damage response signaling mutations) and enrichment of infiltrating immune cells. These results suggest that TNFα-MT may serve as a potential clinical biomarker for NSCLC patients receiving ICIs.

Highlights

Lung cancer is a disease with very high morbidity and mortality among all malignant tumors in the world [1,2,3]
To explore whether the mutation status of the TNFa pathway can predict the prognosis of patients receiving immune checkpoint inhibitors (ICIs) for non-small cell lung cancer (NSCLC), we downloaded the mutation data and survival data of an ICItreated NSCLC cohort from the cBioPortal website [39]
In the ICI-treated cohort, we found that the tumor necrosis factor a signaling mutated (TNFa-MT) group had a significantly higher number of mutations in the double-strand break (DSB), Fanconi anemia (FA), homologous recombination (HR), nucleotide excision repair (NER), nonhomologous end joining (NHEJ), singlestrand break (SSB), and merged DNA damage response (DDR) pathways than the TNFa-WT group

Summary

Introduction

Lung cancer is a disease with very high morbidity and mortality among all malignant tumors in the world [1,2,3]. The 5-year overall survival (OS) rate of patients with advanced lung cancer has been only 5% [4]. Lung cancer is mainly divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC accounts for more than 85% of all lung cancer cases and is the most common histological subtype [5, 6]. The current main treatment plan for NSCLC is a comprehensive treatment based on surgery, radiotherapy, chemotherapy and molecular targeted therapy.

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