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Carcinogenesis. 2018 Dec 31;39(12):1447-1454. doi: 10.1093/carcin/bgy119.

Prognostic modeling of the immune-centric transcriptome reveals interleukin signaling candidates contributing to differential patient outcomes.

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Department of Oncology, Wayne State University, Detroit, MI, USA.
Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA.
Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA.
Department of Biochemistry Microbiology and Immunology, Wayne State University, Detroit, MI, USA.
Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University.
Mucosal Immunology Studies Team, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Detroit, MI, USA.
Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA.
Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI, USA.


Immunotherapy is a promising advancement in the treatment of non-small-cell lung carcinoma (NSCLC), although much of how lung tumors interact with the immune system in the natural course of disease remains unknown. We investigated the impact of the expression of immune-centric genes and pathways in tumors on patient survival to reveal novel candidates for immunotherapeutic research. Tumor transcriptomes and detailed clinical characteristics were obtained from patients with NSCLC who were participants of either the Inflammation, Health and Lung Epidemiology (INHALE) (discovery, N = 280) or The Cancer Genome Atlas (TCGA) Lung (replication, N = 1026) studies. Expressions of 2253 genes derived from 48 major immune pathways were assessed for association with patient prognosis using a multivariable Cox model and pathway effects were assessed with an in-house implementation of the Gene Set Enrichment Analysis (GSEA) algorithm. Prognosis-guided gene and pathway analysis of immune-centric expression in tumors revealed significant survival enrichments across both cohorts. The 'Interleukin Signaling' pathway, containing 430 genes, was found to be statistically and significantly enriched with prognostic signal in both the INHALE (P = 0.008) and TCGA (P = 0.039) datasets. Subsequent leading-edge analysis identified a subset of genes (N = 23) shared between both cohorts, driving the pathway enrichment. Cumulative expression of this leading-edge gene signature was a strong predictor of patient survival [discovery: hazard ratio (HR) = 1.59, P = 3.0 × 10-8; replication: HR = 1.29, P = 7.4 × 10-7]. These data demonstrate the impact of immune-centric expression on patient outcomes in NSCLC. Furthermore, prognostic gene effects were localized to discrete immune pathways, of which Interleukin Signaling had the greatest impact on overall survival and the subset of genes driving these effects have promise for future therapeutic intervention.

[Available on 2019-12-31]

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