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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bacterial Proteins
  • CRISPR-Associated Protein 9
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Cytotoxicity, Immunologic / genetics*
  • DNA-Binding Proteins
  • Endonucleases
  • Genetic Testing
  • HMGB Proteins / genetics
  • HMGB Proteins / metabolism
  • Humans
  • Immunotherapy
  • Interferon-gamma / therapeutic use
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / therapy*
  • Mice
  • Skin Neoplasms / genetics
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / therapy*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • 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