Fig. 3

Patient-specific networks of cooperating DISTs in the tumor microenvironment of metastatic melanomas: Edges are included in the network only if the log2 ratio of the DIST pair is greater than 0.5. Nodes are labeled (e.g. Th2) according the corresponding GIT for the DIST being represented. A Kaplan Meier plot for the ratio between the immune cell pair underlies each edge in the networks, but only two Kaplan Meiers are shown for illustration purposes. Green nodes represent the numerator in the log2 ratio calculation and red nodes in the networks represent the denominator, i.e. that the green immune cell type is present in the patient to a greater degree relative to the red immune cell. An example of a responder patient (OS, 1478 days) is shown, top left. The survival analysis for the whole patient cohort (57 patients), illustrated in the figure reveals a classical Th1 driven tumor-killing microenvironment. The highest quartile (green lines) and the lowest quartile (black lines) of the log2 ratio of the DIST pair are illustrated in the Kaplan-Meier curves. The predicted Th1 cell phenotype [85] is present to a greater extent than Th2 cell phenotype [38] in the network. In addition the responder revealed a greater proportion of cytotoxic CD8+ T cells compared to Th2, revealing a tumor-killing microenvironment network. Conversely, an example of a non-responder patient-specific network (OS, 25 days) is shown (bottom right). Notably, this non-responder hosted a CD8+ cytotoxic T cell subset, low for the checkpoint inhibitor PD-1 [39], to a lesser degree proportional to a T-regulatory cell population DIST [49]. This suggests the presence of a classical immunosuppressive microenvironment in this patient’s tumor. Notably also from the perspective of an immunosuppressive environment is the predicted presence of a higher proportion of a neutrophil DIST population of cells (GSE58173), compared to activated IL2 stimulated NK cells [47]