Format

Send to

Choose Destination
See comment in PubMed Commons below
Cell. 2015 Jan 15;160(1-2):48-61. doi: 10.1016/j.cell.2014.12.033.

Molecular and genetic properties of tumors associated with local immune cytolytic activity.

Author information

1
The Broad Institute, Cambridge, MA 02142, USA; Harvard/MIT Division of Health Sciences and Technology, Cambridge, MA 02141, USA.
2
The Broad Institute, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
3
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.
4
The Broad Institute, Cambridge, MA 02142, USA; Massachusetts General Hospital Cancer Center and Department of Pathology, Charlestown, MA 02129, USA.
5
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.

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.

PMID:
25594174
PMCID:
PMC4856474
DOI:
10.1016/j.cell.2014.12.033
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center