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PMID: 25594174 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Cell ·Vol. 160 ·No. 1-2 ·2015-01-15 ·Pages 48-61

Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N

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.

MeSH Terms
Antigen Presentation Antigens, Neoplasm/immunology Apoptosis DNA Copy Number Variations Databases, Genetic Endogenous Retroviruses Genome, Human Humans Mutation Necrosis Neoplasms/immunology,pathology T-Lymphocytes, Cytotoxic/immunology
Chemicals
Antigens, Neoplasm
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Rooney Michael S
The Broad Institute, Cambridge, MA 02142, USA; Harvard/MIT Division of Health Sciences and Technology, Cambridge, MA 02141, USA.
Shukla Sachet A
The Broad Institute, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Wu Catherine J
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.
Getz Gad
The Broad Institute, Cambridge, MA 02142, USA; Massachusetts General Hospital Cancer Center and Department of Pathology, Charlestown, MA 02129, USA.
Hacohen Nir
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: [email protected].
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2014.12.033
Email
[email protected]
Published
2015-01-15
Pages
48-61
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4856474
Subset
IM
Grants
NIH HHS · DP2 OD002230 · United States
NCI NIH HHS · R01 CA155010 · United States
NHGRI NIH HHS · T32 HG002295 · United States
Corrections
CommentIn
PMID: 25668786
External Links
PubMed source DOI: 10.1016/j.cell.2014.12.033 PMC Full Text View journal details
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