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BPTF Depletion Enhances T-cell-Mediated Antitumor Immunity

Kimberly Mayes1, Suehyb G Alkhatib1, Kristen Peterson1

  • 1Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.

Cancer Research
|September 22, 2016
PubMed

Insights

Targeting the nucleosome remodeling factor (NURF) complex by disabling its bromodomain PHD-finger containing transcription factor (BPTF) subunit enhances antitumor immunity. This approach improves T-cell activity and antigen processing, suggesting NURF as a therapeutic target.

Area of Science:

  • Immunology
  • Cancer Research
  • Chromatin Biology

Background:

  • The nucleosome remodeling factor (NURF) complex, implicated in fruit fly immunity, has not been studied in mammalian systems.
  • Understanding NURF's role in mammalian immunity is crucial for developing novel cancer therapies.

Purpose of the Study:

  • To investigate the role of NURF in mammalian antitumor immunity.
  • To determine if targeting NURF can enhance the immune response against cancer.

Main Methods:

  • NURF was disabled in mice by silencing its essential subunit, bromodomain PHD-finger containing transcription factor (BPTF).
  • Antitumor immunity was assessed in syngeneic cancer models using CD8+ and CD4+ T cell analysis.
  • Mechanistic studies involved examining gene expression of immunoproteasome and antigen transporter components, and using a PSMB8 inhibitor.

Main Results:

  • Disabling BPTF significantly enhanced antitumor immunity in mice.
  • Elevated numbers of activated CD8+ T cells and enhanced cytolytic activity were observed in BPTF-deficient tumors, suggesting novel antigen involvement.
  • NURF was found to directly regulate genes involved in antigen processing (Psmb8, Psmb9, Tap1, Tap2), and inhibition of PSMB8 reversed the enhanced immunity.

Conclusions:

  • NURF normally suppresses tumor antigenicity; its depletion enhances antigen processing and CD8 T-cell cytotoxicity.
  • Targeting NURF improves antitumor immunity, identifying it as a potential therapeutic target for cancer immunotherapy.
  • The immunoproteasome plays a critical role in the enhanced antitumor immunity observed upon NURF ablation.

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