AUTHOR=Dong Chunyu , Dang Dan , Zhao Xuesong , Wang Yuanyuan , Wang Zhijun , Zhang Chuan 

TITLE=Integrative Characterization of the Role of IL27 In Melanoma Using Bioinformatics Analysis

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.713001

DOI=10.3389/fimmu.2021.713001

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p><italic>IL27</italic> has been reported to play dual roles in cancer; however, its effects on the tumor microenvironment (TME), immunotherapy, and prognosis in melanoma remain largely unclear. This study was aimed to uncover the effects of <italic>IL27</italic> on TME, immunotherapy and prognosis in patients with melanoma.</p></sec><sec><title>Methods</title><p>RNA-seq data, drug sensitivity data, and clinical data were obtained from TCGA, GEO, CCLE, and CTRP. Log-rank test was used to determine the survival value of <italic>IL27</italic>. Univariate and multivariate Cox regression analyses were employed to determine the independent predictors of survival outcomes. DAVID and GSEA were used to perform gene set functional annotations. ssGSEA was used to explore the association between <italic>IL27</italic> and immune infiltrates. ConsensusClusterPlus was used to classify melanoma tissues into hot tumors or cold tumors.</p></sec><sec><title>Results</title><p>Clinically, <italic>IL27</italic> was negatively correlated with Breslow depth (<italic>P</italic> = 0.00042) and positively associated with response to radiotherapy (<italic>P</italic> = 0.038). High <italic>IL27</italic> expression showed an improved survival outcome (<italic>P</italic> = 0.00016), and could serve as an independent predictor of survival outcomes (hazard ratio: 0.32 - 0.88, <italic>P</italic> = 0.015). Functionally, elevated <italic>IL27</italic> expression could induce an enhanced immune response and pyroptosis (<italic>R</italic> = 0.64, <italic>P</italic> = 1.2e-55), autophagy (<italic>R</italic> = 0.37, <italic>P</italic> = 7.1e-17) and apoptosis (<italic>R</italic> = 0.47, <italic>P</italic> = 1.1e-27) in patients with melanoma. Mechanistically, elevated <italic>IL27</italic> expression was positively correlated with cytotoxic cytokines (including <italic>INFG</italic> and <italic>GZMB</italic>), enhanced immune infiltrates, and elevated CD8/Treg ratio (<italic>R</italic> = 0.14, <italic>P</italic> = 0.02), possibly driving CD8<sup>+</sup> T cell infiltration by suppressing β-catenin signaling in the TME. Furthermore, <italic>IL27</italic> was significantly associated with hot tumor state, multiple predictors of response to immunotherapy, and improved drug response in patients with melanoma.</p></sec><sec><title>Conclusions</title><p><italic>IL27</italic> was correlated with enriched CD8<sup>+</sup> T cells, desirable therapeutic response and improved prognosis. It thus can be utilized as a promising modulator in the development of cytokine-based immunotherapy for melanoma.</p></sec>