title: Molecular and genetic properties of tumors associated with local immune cytolytic activity.
abstract: 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.
authors.affiliation: The Broad Institute, Cambridge, MA 02142, USA; Harvard/MIT Division of Health Sciences and Technology, Cambridge, MA 02141, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Rooney
authors.affiliation: The Broad Institute, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Sachet A
authors.initials: SA
authors.lastname: Shukla
authors.affiliation: The Broad Institute, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: The Broad Institute, Cambridge, MA 02142, USA; Massachusetts General Hospital Cancer Center and Department of Pathology, Charlestown, MA 02129, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: The Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Center for Immunology and Inflammatory Diseases and Department of Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA. Electronic address: nhacohen@mgh.harvard.edu.
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
mesh_terms: D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology; D017209:Apoptosis; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D020077:Endogenous Retroviruses; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D009336:Necrosis; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm