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PMID: 29301958 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

Science (New York, N.Y.) ·Vol. 359 ·No. 6377 ·2018-00-16 ·Pages 770-775

Pan D, Kobayashi A, Jiang P, Ferrari de Andrade L, Tay RE, Luoma AM, Tsoucas D, Qiu X, Lim K, Rao P, Long HW, Yuan GC, Doench J, Brown M, Liu XS, Wucherpfennig KW

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.

MeSH Terms
Animals Bacterial Proteins CRISPR-Associated Protein 9 CRISPR-Cas Systems Cell Line, Tumor Chromosomal Proteins, Non-Histone/genetics,metabolism Cytotoxicity, Immunologic/genetics DNA-Binding Proteins Endonucleases Genetic Testing HMGB Proteins/genetics,metabolism Humans Immunotherapy Interferon-gamma/therapeutic use Melanoma, Experimental/genetics,immunology,therapy Mice Skin Neoplasms/genetics,immunology,therapy T-Lymphocytes, Cytotoxic/immunology Transcription Factors/genetics,metabolism
Chemicals
Bacterial Proteins Brd7 protein, mouse Chromosomal Proteins, Non-Histone DNA-Binding Proteins HMGB Proteins Pbrm1 protein, mouse SWI-SNF-B chromatin-remodeling complex Transcription Factors Interferon-gamma CRISPR-Associated Protein 9 Cas9 endonuclease Streptococcus pyogenes Endonucleases
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Pan Deng ORCID
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Kobayashi Aya ORCID
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. | Astellas Pharma, Tokyo 103-8411, Japan.
Jiang Peng ORCID
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Ferrari de Andrade Lucas ORCID
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Tay Rong En
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Luoma Adrienne M
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Tsoucas Daphne
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Qiu Xintao ORCID
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Lim Klothilda ORCID
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Rao Prakash
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Long Henry W ORCID
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Yuan Guo-Cheng
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Doench John ORCID
Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Brown Myles
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Liu X Shirley ORCID
Astellas Pharma, Tokyo 103-8411, Japan. kai_wucherpfennig@dfci.harvard.edu xsliu@jimmy.harvard.edu.
Wucherpfennig Kai W ORCID
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. kai_wucherpfennig@dfci.harvard.edu xsliu@jimmy.harvard.edu. | Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.aao1710
Email
kai_wucherpfennig@dfci.harvard.edu
xsliu@jimmy.harvard.edu
Published
2018-00-16
Epub
2018-00-04
Pages
770-775
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC5953516
Subset
IM
Grants
NCI NIH HHS · R01 CA173750 · United States
NCI NIH HHS · U24 CA224316 · United States
NIGMS NIH HHS · T32 GM074897 · United States
NHGRI NIH HHS · R01 HG008927 · United States
NCI NIH HHS · T32 CA207021 · United States
Corrections
CommentIn
PMID: 29449480
External Links
PubMed source DOI: 10.1126/science.aao1710 PMC Full Text View journal details
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