Format

Send to

Choose Destination
Nature. 2017 Aug 31;548(7669):537-542. doi: 10.1038/nature23477. Epub 2017 Aug 7.

Identification of essential genes for cancer immunotherapy.

Author information

1
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
2
NIH-Georgetown University Graduate Partnership Program, Georgetown University Medical School, Washington DC 20057, USA.
3
New York Genome Center, New York, New York 10013, USA.
4
Department of Biology, New York University, New York, New York 10012, USA.
5
Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
6
Children's Hospital of Philadelphia and Department of Genetics, University of Pennsylvania, Pennsylvania 19104, USA.
7
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
8
McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
9
Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.

Abstract

Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR-Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8+ T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8+ T cells with the resistance or non-responsiveness of cancer to immunotherapies.

PMID:
28783722
PMCID:
PMC5870757
DOI:
10.1038/nature23477
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center