title: Profiling networks of distinct immune-cells in tumors.
abstract: BACKGROUND
  It is now clearly evident that cancer outcome and response to therapy is guided by diverse immune-cell activity in tumors. Presently, a key challenge is to comprehensively identify networks of distinct immune-cell signatures present in complex tissue, at higher-resolution and at various stages of differentiation, activation or function. This is particularly so for closely related immune-cells with diminutive, yet critical, differences.
  
  
  RESULTS
  To predict networks of infiltrated distinct immune-cell phenotypes at higher resolution, we explored an integrated knowledge-based approach to select immune-cell signature genes integrating not only expression enrichment across immune-cells, but also an automatic capture of relevant immune-cell signature genes from the literature. This knowledge-based approach was integrated with resources of immune-cell specific protein networks, to define signature genes of distinct immune-cell phenotypes. We demonstrate the utility of this approach by profiling signatures of distinct immune-cells, and networks of immune-cells, from metastatic melanoma patients who had undergone chemotherapy. The resultant bioinformatics strategy complements immunohistochemistry from these tumors, and predicts both tumor-killing and immunosuppressive networks of distinct immune-cells in responders and non-responders, respectively. The approach is also shown to capture differences in the immune-cell networks of BRAF versus NRAS mutated metastatic melanomas, and the dynamic changes in resistance to targeted kinase inhibitors in MAPK signalling.
  
  
  CONCLUSIONS
  This integrative bioinformatics approach demonstrates that capturing the protein network signatures and ratios of distinct immune-cell in the tumor microenvironment maybe an important factor in predicting response to therapy. This may serve as a computational strategy to define network signatures of distinct immune-cells to guide immuno-pathological discovery.
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. trevor.clancy@rr-research.no.|Department of Cancer Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. trevor.clancy@rr-research.no.
authors.forename: Trevor
authors.identifier: http://orcid.org/0000-0001-9896-0613
authors.initials: T
authors.lastname: Clancy
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Biomedical Research Group, Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.|Institute of Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Eivind
authors.initials: E
authors.lastname: Hovig
mesh_terms: D019295:Computational Biology / Q000379:methods*; D020558:GTP Phosphohydrolases / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D007107:Immune System / Q000276:immunology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000235:genetics* / Q000276:immunology* / Q000556:secondary; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: Cancer; Immune informatics; Immune profiling; Immune-cell infiltration; Personalized medicine; Protein interaction networks; Transcriptomics