Purpose: Throughout their development tumors are challenged by the immune system and they acquire features to evade its surveillance. A systematic view of these traits which sheds light on how tumors respond to immunotherapies is still lacking. Experimental Design: Here, we computed the relative abundance of an array of immune cell populations to measure the immune infiltration pattern of 9,174 tumors of 29 solid cancers. We then clustered tumors with similar infiltration pattern to define immune-phenotypes. Finally, we identified genomic and transcriptomic traits associated to these immune-phenotypes across cancer types. Results: In highly cytotoxic immune-phenotypes we found tumors with low clonal heterogeneity enriched for alterations of genes involved in epigenetic regulation, ubiquitin mediated proteolysis, antigen-presentation and cell-cell communication, which may drive resistance in combination with the ectopic expression of negative immune checkpoints. Tumors with immune-phenotypes of intermediate cytotoxicity are characterized by an up-regulation of processes involved in neighboring tissue invasion and remodeling that may foster the recruitment of immune-suppressive cells. Tumors with poorly cytotoxic immune-phenotype tend to be of more advanced stages and bear a greater burden of copy number alterations and frequent alterations of cell cycle, hedgehog, beta-catenin and TGF-beta pathways, which may cause immune depletion. Conclusions: We provide a comprehensive landscape of the characteristics of solid tumors that may influence (or be influenced by) the characteristics of their immune infiltrate. These results may help interpret the response of solid tumors to immunotherapies and guide the development of novel drug combination strategies.
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