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CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex

Yanxun Lin1, Huan Jin1, Yong She1

  • 1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510050, China.

Proceedings of the National Academy of Sciences of the United States of America
|January 30, 2025
PubMed

Insights

Chromobox 2 (CBX2) suppresses anti-tumor immunity by inhibiting interferon signaling through a noncanonical complex. Inhibiting CBX2 enhances cancer immunotherapy efficacy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Chromobox 2 (CBX2) is a component of the polycomb repressive complex (PRC) involved in cancer development.
  • The role of CBX2 in regulating tumor immunogenicity and immune evasion is not well understood.

Purpose of the Study:

  • To investigate the function of CBX2 in tumor immunity and its potential as a therapeutic target.
  • To elucidate the molecular mechanisms by which CBX2 influences the tumor immune microenvironment.

Main Methods:

  • Utilized murine syngeneic tumor models to assess the impact of CBX2 ablation on tumor growth and immune response.
  • Conducted transcriptional program analysis and mass spectrometry to identify CBX2-interacting proteins and regulatory pathways.
  • Investigated the interaction of CBX2 with RACK1 and HDAC1 and its effect on H3K27ac modification.

Main Results:

  • CBX2 ablation inhibited tumor growth, activated the tumor immune microenvironment, and enhanced anti-PD1 and adoptive T cell therapy efficacy.
  • CBX2 was found to suppress interferon signaling independently of its canonical PRC function.
  • CBX2 directly interacts with RACK1 and recruits HDAC1 to attenuate H3K27ac on interferon-stimulated gene promoters, suppressing interferon signaling.

Conclusions:

  • CBX2 suppresses tumor immunogenicity and promotes immune evasion via a noncanonical CBX2-RACK1-HDAC1 corepressor complex.
  • High CBX2 expression correlates with an immunosuppressive tumor microenvironment and reduced immunotherapy efficacy in human cancers.
  • The CBX2-RACK1-HDAC1 complex represents a potential therapeutic target and biomarker for cancer immunotherapy.
Keywords:
CBX2immunogenicityimmunotherapyinterferon

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