A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing.
Science
; 359(6377): 770-775, 2018 02 16.
Article
in En
| MEDLINE
| ID: mdl-29301958
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Skin Neoplasms
/
Transcription Factors
/
Melanoma, Experimental
/
Chromosomal Proteins, Non-Histone
/
T-Lymphocytes, Cytotoxic
/
Cytotoxicity, Immunologic
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Science
Year:
2018
Document type:
Article
Affiliation country:
United States