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A Gene Signature Predicting Natural Killer Cell Infiltration and Improved Published OnlineFirst May 14, 2019; DOI: 10.1158/2326-6066.CIR-18-0500 Research Article Cancer Immunology Research A Gene Signature Predicting Natural Killer Cell Infiltration and Improved Survival in Melanoma Patients Joseph Cursons1,2, Fernando Souza-Fonseca-Guimaraes2,3, Momeneh Foroutan1,4, Ashley Anderson1,Fred eric Hollande4, Soroor Hediyeh-Zadeh1, Andreas Behren5,6, Nicholas D. Huntington2,3,7, and Melissa J. Davis1,2,8 Abstract Natural killer (NK) cell activity is essential for initiating (TCGA), we show that patients with metastatic cutaneous antitumor responses and may be linked to immunotherapy melanoma have an improved survival rate if their tumor success. NK cells and other innate immune components shows evidence of NK cell infiltration. Furthermore, these could be exploitable for cancer treatment, which drives the survival effects are enhanced in tumors that show higher need for tools and methods that identify therapeutic ave- expression of genes that encode NK cell stimuli such as the nues. Here, we extend our gene-set scoring method singscore cytokine IL15. Using this signature, we then examine tran- to investigate NK cell infiltration by applying RNA-seq scriptomic data to identify tumor and stromal components analysis to samples from bulk tumors. Computational that may influence the penetrance of NK cells into solid methods have been developed for the deconvolution of tumors. Our results provide evidence that NK cells play a immune cell types within solid tumors. We have taken the role in the regulation of human tumors and highlight NK cell gene signatures from several such tools, then curated potential survival effects associated with increased NK cell the gene list using a comparative analysis of tumors and activity. Our computational analysis identifies putative gene immune cell types. Using a gene-set scoring method to targets that may be of therapeutic value for boosting NK cell investigate RNA-seq data from The Cancer Genome Atlas antitumor immunity. Introduction lung cancer (2), hematologic malignancies (3), and melano- ma (4). Although these treatments show promise, their efficacy Immunotherapies have improved clinical treatment for several is restricted to a subset of tumor types and patients with "immune cancer types, including renal cell carcinoma (1), non–small cell hot" tumors. Improved understanding of how the innate immune system contributes to antitumor responses can help to open new 1 Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, therapeutic avenues, to increase the potential and efficacy of Parkville, Victoria, Australia. 2Department of Medical Biology, Faculty of Med- clinical treatments, and to expand the range of targeted malig- icine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia. 3Division of Molecular Immunology, Walter and Eliza Hall Institute of nancies. Natural killer (NK) cells, a subset of innate lymphoid Medical Research, Parkville, Victoria, Australia. 4Department of Clinical Pathol- cells, are effectors of innate immunity. The cytotoxic capabilities ogy, The University of Melbourne Centre for Cancer Research, Victorian Com- of NK cells allow them to kill tumor cells even at a relatively low prehensive Cancer Centre, Melbourne, Victoria, Australia. 5School of Cancer ratio (e.g., 1:1; ref. 5). NK cells are necessary for clearance of cells 6 Medicine, La Trobe University, Melbourne, Victoria, Australia. Olivia Newton- that carry a viral burden or have undergone oncogenic transfor- John Cancer Research Institute, Heidelberg, Victoria, Australia. 7Biomedicine mation, and several in vivo studies have demonstrated a role for Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. 8Department of Biochemistry, NK cells in limiting the metastatic dissemination of melano- Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, ma (6–9). NK cells can be targeted by immunotherapeu- Parkville, Victoria, Australia. tics (10, 11). Furthermore, NK cells can initiate an antitumor Note: Supplementary data for this article are available at Cancer Immunology T-cell response by recruiting conventional type-1 dendritic Research Online (http://cancerimmunolres.aacrjournals.org/). cells (cDC1) through chemokine signaling (via XCL-1 and J. Cursons and F. Souza-Fonseca-Guimaraes contributed equally to this article. CCL5/RANTES; ref. 12), and support stimulatory DCs (sDC) through the expression of the Flt3 ligand (Flt3l in mice and N.D. Huntington and M.J. Davis contributed equally to this article. FLT3LG in humans; ref. 13). Corresponding Authors: Melissa J. Davis, Walter and Eliza Hall Institute of Regulators of NK cell activity include the cytokine IL15 (14), Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC 3052, Australia. chemokines such as CCL5 (RANTES; ref. 15), growth factors such Phone: 61-3-9345-2597; Fax: 61-3-9347-0852; E-mail: [email protected]; as TGFb (16, 17), and cytokine-inducible SH2 containing protein and Nicholas D. Huntington. Phone: 61-3-9902-4239; E-mail: – [email protected] (CIS), which modulates intracellular JAK STAT signaling (18). Evidence suggests that modulation of NK cell populations is Cancer Immunol Res 2019;7:1162–74 feasible for cancer treatment (19). Treatments based upon sys- doi: 10.1158/2326-6066.CIR-18-0500 temic administration of IL15 constructs have shown promise in Ó2019 American Association for Cancer Research. leukemic and solid tumors (20–22). Although IL15 alone can 1162 Cancer Immunol Res; 7(7) July 2019 Downloaded from cancerimmunolres.aacrjournals.org on September 16, 2019. © 2019 American Association for Cancer Research. Published OnlineFirst May 14, 2019; DOI: 10.1158/2326-6066.CIR-18-0500 A Gene Signature for NK Infiltration and Melanoma Survival stimulate immune targeting of cancers, cytokine-mediated NK cell NK cell samples (Supplementary Fig. S1A), a principal compo- activation and expansion can be increased in combination nent analysis (PCA) indicated that the CD56LoCD16Hi NK cell with IL12 and IL18 (23) or further amplified through deletion samples showed separation from other NK cell samples on PC1 of CIS (encoded by CISH), a negative regulator of cytokine and PC3 (Supplementary Fig. S1B) with several samples cluster- À À signaling and effector function. Cish / mice are resistant to a ing toward granulocytes and monocytes on PC4 (Supplementary range of metastatic cancers (18). Thus, it is clear that we are yet to Fig. S1C). In cases with gene multimapping (multiple probes/ fully elucidate the full repertoire of molecular systems that reg- probe sets per gene), median values were used. To better examine ulate in vivo NK cell activity. the relative expression of marker genes across immune cell sub- þ Advances in nucleic acid sequencing technology and associ- sets, we examined CD45 ("nonmalignant") single-cell RNA-seq ated methods for data analysis have allowed the application of data from dissociated melanoma samples with annotated cell transcriptomic profiling to complex tumor samples (24, 25). types (GSE72056; ref. 36). Further, single-cell RNA-seq from Resulting data have enabled the development of mathematical (checkpoint inhibition na€ve) dissociated melanoma samples methods, such as CIBERSORT (26), that infer the relative (GSE120575; ref. 37) were used for subsequent comparison and abundance of immune cells that have infiltrated into solid visualization. tumor samples. Although these tools have improved our under- standing of immune infiltration (27–30) and advanced cancer Microarray data relative log expression and PCA research, the complexity of model fitting procedures makes it Using relative log expression (RLE) plots to explore unwanted difficult for researchers to modify or investigate these gene lists. variation (38), log-transformed transcript abundance data In addition, public tumor transcriptomic data offer opportu- (downloaded directly from GEO) were median-centered for each nities to identify how changes in tumor phenotype are associ- gene, and then within each sample the difference between the ated with changes in the relative abundance of immune cell observed and population median of each gene was calculated. For subpopulations. the PCA, genes with abundance above the 10th percentile (5.34) We have developed a single-sample gene-set scoring method within at least 4 samples (corresponding to the smallest sample that uses a rank-based metric to quantify the relative enrichment group) were retained. Data were normalized using sklearn Stan- of a gene set within a sample transcriptome (31). Here, we have dardScaler, before calculating principal components using the combined NK cell signatures from the LM22/CIBERSORT (26) sklearn PCA function. and LM7 (32) gene sets and curated this list to produce a gene set that reflects the relative abundance of NK cells within a tumor Immune gene sets and previous classifications sample. As melanoma tumor cells are highly immunogenic, we Genes identified in Fig. 1 were annotated as immune-associated have focused upon the analysis of TCGA skin cutaneous mela- using the Gene Ontology category GO:0002376—"immune system noma (SKCM) data (33). We show that the relative expression of process"—together with all descendant or child processes (39). The NK cell genes within metastatic tumors is associated with a original SKCM manuscript (33) was used for the associated TCGA survival advantage. Our scoring approach can be used
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