A Pan-cancer Landscape of Interactions between Solid Tumors and Infiltrating Immune Cell Populations

<b>Purpose:</b> 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 shed light on how tumors respond to immunotherapies, is still lacking.<b>Experimental Design:</b> 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 immunophenotypes. Finally, we identified genomic and transcriptomic traits associated to these immunophenotypes across cancer types.<b>Results:</b> In highly cytotoxic immunophenotypes, 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 immunophenotypes of intermediate cytotoxicity are characterized by an upregulation of processes involved in neighboring tissue invasion and remodeling that may foster the recruitment of immunosuppressive cells. Tumors with poorly cytotoxic immunophenotype tend to be of more advanced stages and bear a greater burden of copy number alterations and frequent alterations of cell cycle, hedgehog, β-catenin, and TGFβ pathways, which may cause immune depletion.<b>Conclusions:</b> 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. <i>Clin Cancer Res; 24(15); 3717-28. ©2018 AACR</i>.