A bioinformatics approach to uncover the role of Tumor Associated Macrophages and their polarization-specific regulators in melanoma
Emilia Maria Cristina Mazza1*, Enrico Lugli1
1Laboratory of Translational Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
Immune cells represent a substantial component of the tumor mass but their proportion and the crosstalk between them are unclear. For example, previous study demonstrated that in growing tumours, Tumour Associated Macrophages (TAMs) hamper antitumour T cell functions, but the exact mechanism through which they do that is unknown. The role of TAMs however is ambivalent because they can produce molecules that protect tumour cells from being killed by CD8+ T cell activity. However, at the same time molecules expressed by Macrophages have a Key role in boosting T-cell therapies. Ipilimumab (anti-cytotoxic T-lymphocyte-associated antigen 4), which amplifies antitumour T cell activity while restricting immunosuppressive Tregcells, reduces Treg cell counts via FcγR-mediated phagocytosis. The ambivalent behavior of TAMs is possible due the fact that in the tumor coexist pro e antitumor TAMs. Here we report the application of computational methods to Identify specific markers and master regulatory genes of the different subgroups of TAMs. Specifically, starting from the gene expression analysis of M1 and M2 in vitro polarized macrophages, two signatures composed by genes that reflect the two different activations were obtained. These two signatures can be used to label macrophages from a melanoma single cell sequencing experiment.Next, using an ad-hoc procedure is possible to obtain genes that characterize M1 cytotoxic and M2 tolerant macrophages in the tumor. Through enrichment analysis and overrepresentation analysis of transcription factor (TF) binding site motifs, we identified subsets of M1 or M2 related genes and TFs that can be considered as process controllers.The identification of these master regulators of the different subset of Macrophages can lead to selective TAMs depletion strategies.
Funding: E.M.C.M. was supported by Fondazione Veronesi (Milan, Italy)