Arid3b suppresses CD8+T cell infiltration and function in microsatellite-stable colorectal cancer via Runx3

Shuo Wang1,2, Sen Hou1,2, Ce Luo3

  • 1Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China.

Insights

Targeting ARID3B in T cells enhances their infiltration into microsatellite-stable colorectal cancer (MSS CRC) tumors. This boosts anti-tumor activity and improves immunotherapy response in MSS CRC models.

Area of Science:

  • Immunology
  • Oncology
  • Genetics

Background:

  • Microsatellite-stable colorectal cancer (MSS CRC) exhibits a "cold" tumor microenvironment, hindering CD8+ T cell infiltration and limiting efficacy of immune checkpoint inhibitors (ICIs).
  • Identifying novel regulators of T cell infiltration is crucial for overcoming immunotherapy resistance in MSS CRC.

Purpose of the Study:

  • To identify key regulators of CD8+ T cell infiltration in MSS CRC.
  • To explore the therapeutic potential of targeting these regulators to enhance anti-tumor immunity.

Main Methods:

  • Conducted an in vivo CRISPR/Cas9 screen in a CMT93 cell-derived murine tumor model.
  • Utilized genetic ablation of Arid3b in CD8+ T cells.
  • Investigated the role of Runx3 in mediating the effects of Arid3b deficiency.

Main Results:

  • Identified Arid3b as a critical negative regulator of CD8+ T cell infiltration and anti-tumor activity.
  • Genetic ablation of Arid3b in CD8+ T cells significantly increased their accumulation within tumors and promoted tumor control.
  • Arid3b deficiency upregulated Runx3, inducing a tissue-resident memory-like phenotype and enhancing effector function in a Runx3-dependent manner.

Conclusions:

  • Targeting ARID3B in CD8+ T cells represents a promising strategy to enhance anti-tumor immunity in MSS CRC.
  • Modulating ARID3B can reshape the tumor microenvironment, potentially sensitizing MSS CRC to immunotherapy.

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