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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.