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Science. 2018 Feb 16;359(6377):770-775. doi: 10.1126/science.aao1710. Epub 2018 Jan 4.

A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing.

Author information

1
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
2
Astellas Pharma, Tokyo 103-8411, Japan.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
5
Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
6
Astellas Pharma, Tokyo 103-8411, Japan. kai_wucherpfennig@dfci.harvard.edu xsliu@jimmy.harvard.edu.
7
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. kai_wucherpfennig@dfci.harvard.edu xsliu@jimmy.harvard.edu.
8
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.

Abstract

Many human cancers are resistant to immunotherapy, for reasons that are poorly understood. We used a genome-scale CRISPR-Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of >100 genes-including Pbrm1, Arid2, and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex-sensitized mouse B16F10 melanoma cells to killing by T cells. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.

Comment in

PMID:
29301958
PMCID:
PMC5953516
DOI:
10.1126/science.aao1710
[Indexed for MEDLINE]
Free PMC Article

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