Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity

How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic data sets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2-microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity. [Display omitted] •Analysis of 18 TCGA tumor types shows genomic correlates of immune cytolytic activity•Multiple tumor types demonstrate strong link between mutation load and local immunity•Infiltrated tumors are enriched for probable escape lesions affecting CASP8, HLA, B2M•Copy number changes in suppressive PDL1, ALOX12B/15B are also tied to immune activity A systematic survey of 18 TCGA tumor types reveals how the mutational load of tumors shapes and is shaped by the ongoing immune response, identifying sequence changes and copy number amplifications that favor immune evasion, as well as point mutations that are associated with high cytolytic activity and can be explored as targets for immunotherapy.