Identification and validation of tumor environment phenotypes in lung adenocarcinoma by integrative genome-scale analysis

Mar 20, 2020Cancer immunology, immunotherapy : CII

Identifying and confirming tumor environment types in lung adenocarcinoma using large-scale genetic analysis

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

A dataset of 1411 lung adenocarcinoma patients revealed two distinct tumor microenvironment clusters.

TMEcluster A exhibited sparse immune cell infiltration, lower levels of immunomodulators, and a slightly higher mutation load.
TMEcluster B showed enrichment of cytotoxic T cells and immunosuppressor cells, along with increased levels of immune-related cytokines and checkpoint molecules.
The TME cluster was identified as an independent prognostic factor, with TMEcluster B associated with a hazard ratio of 0.68 for better outcomes compared to TMEcluster A.
The findings were validated using external data from the GEO database and additional samples from the institution.

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PURPOSE: To comprehensively elucidate the landscape of the tumor environment (TME) of lung adenocarcinoma (LUAD), which has a profound impact on prognosis and response to immunotherapy.

METHODS AND MATERIALS: Using a large dataset of LUAD patients from The Cancer Genome Atlas, Gene Expression Omnibus database (GEO), and our institution (n = 1411), we estimated the infiltration pattern of 24 immune cell populations in each sample and systematically correlated the TME phenotypes with genomic traits and clinicopathologic characteristics.

RESULTS: The LUAD microenvironment was classified into two distinct TME clusters (A and B), and a random forest classifier model was constructed. TMEcluster A was characterized by sparse distribution of immune cell infiltration, relatively low levels of immunomodulators and slightly higher mutation load. By contrast, enrichment of both cytotoxic T cells and immunosuppressor cells was observed in TMEcluster B. Moreover, several immune-related cytokines or markers including IFN-γ, TNF-β, and several immune checkpoint molecules such as PD-L1 were also upregulated in TMEcluster B. Multivariable Cox analysis revealed that the TMEcluster was an independent prognostic factor (TMEcluster B vs. A, hazard ratio = 0.68, 95% confidence interval = 0.50-0.91, p = 0.010). These findings were all externally validated in the data from the GEO database and our institution.

CONCLUSIONS: Our findings describe a comprehensive landscape of LUAD immune infiltration pattern and integrate several previously proposed biomarkers associated with distinct immunophenotypes, thus shedding light on how tumors interact with immune microenvironment. Our results may guide a more precise immune therapeutic strategy for LUAD patients.

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Identification and validation of tumor environment phenotypes in lung adenocarcinoma by integrative genome-scale analysis

Abstract

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