A Gene Signature Predicting Natural Killer Cell Infiltration and Improved Survival in Melanoma Patients

被引:193
|
作者
Cursons, Joseph [1 ,2 ]
Souza-Fonseca-Guimaraes, Fernando [2 ,3 ]
Foroutan, Momeneh [1 ,4 ]
Anderson, Ashley [1 ]
HoHande, Frederic [4 ]
Hediyeh-Zadeh, Soroor [1 ]
Behren, Andreas [5 ,6 ]
Huntington, Nicholas D. [2 ,3 ,7 ,8 ]
Davis, Melissa J. [1 ,2 ,9 ]
机构
[1] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic, Australia
[2] Univ Melbourne, Dept Med Biol, Fac Med Dent & Hlth Sci, Parkville, Vic, Australia
[3] Walter & Eliza Hall Inst Med Res, Div Mol Immunol, Parkville, Vic, Australia
[4] Univ Melbourne, Ctr Canc Res, Dept Clin Pathol, Victorian Comprehens Canc Ctr, Melbourne, Vic, Australia
[5] La Trobe Univ, Sch Canc Med, Melbourne, Vic, Australia
[6] Olivia Newton John Canc Res Inst, Heidelberg, Vic, Australia
[7] Monash Univ, Biomed Discovery Inst, Clayton, Vic, Australia
[8] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia
[9] Univ Melbourne, Dept Biochem, Fac Med Dent & Hlth Sci, Parkville, Vic, Australia
基金
澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;
关键词
IL-15 SUPERAGONIST COMPLEX; NK CELLS; PD-1; BLOCKADE; CHECKPOINT; RESISTANCE; EXPRESSION; PHENOTYPE; PROMOTES; IMMUNOTHERAPIES; CLASSIFICATION;
D O I
10.1158/2326-6066.CIR-18-0500
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Natural killer (NK) cell activity is essential for initiating antitumor responses and may be linked to immunotherapy success. NK cells and other innate immune components could be exploitable for cancer treatment, which drives the need for tools and methods that identify therapeutic avenues. Here, we extend our gene-set scoring method singscore to investigate NK cell infiltration by applying RNA-seq analysis to samples from bulk tumors. Computational methods have been developed for the deconvolution of immune cell types within solid tumors. We have taken the NK cell gene signatures from several such tools, then curated the gene list using a comparative analysis of tumors and immune cell types. Using a gene-set scoring method to investigate RNA-seq data from The Cancer Genome Atlas (TCGA), we show that patients with metastatic cutaneous melanoma have an improved survival rate if their tumor shows evidence of NK cell infiltration. Furthermore, these survival effects are enhanced in tumors that show higher expression of genes that encode NK cell stimuli such as the cytokine IL15. Using this signature, we then examine transcriptomic data to identify tumor and stromal components that may influence the penetrance of NK cells into solid tumors. Our results provide evidence that NK cells play a role in the regulation of human tumors and highlight potential survival effects associated with increased NK cell activity. Our computational analysis identifies putative gene targets that may be of therapeutic value for boosting NK cell antitumor immunity.
引用
收藏
页码:1162 / 1174
页数:13
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