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Enforced expression of Runx3 improved CAR-T cell potency in solid tumor via enhancing resistance to

Yi Wang1, Honghong Zhang2, Guoxiu Du2

  • 1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China; CARsgen Therapeutics Co., Ltd, Shanghai 200231, China.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|December 16, 2022
PubMed

Insights

Overexpressing Runx3 in chimeric antigen receptor (CAR)-T cells enhances their persistence and antitumor activity in solid tumors. This Runx3 modification improves CAR-T cell survival and efficacy, offering a promising new treatment strategy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cell Therapy

Background:

  • Chimeric antigen receptor (CAR)-T cell therapy faces challenges with T cell persistence in solid tumors.
  • Strategies to enhance T cell persistence, such as cytokine secretion, are known, but others remain understudied.
  • Runx3 is a key regulator of T cell development, cytotoxic differentiation, and tissue-resident memory T (Trm) cell formation.

Purpose of the Study:

  • To investigate the potential of Runx3 overexpression to improve CAR-T cell persistence and efficacy in solid tumors.
  • To evaluate the impact of Runx3 coexpression on CAR-T cell antitumor activities in vivo and in vitro.

Main Methods:

  • Generation of CAR-T cells overexpressing Runx3 (Run-CAR-T cells).
  • Assessment of CAR-T cell persistence, proliferation, and effector functions in a mouse model of solid tumors.
  • In vitro analysis of Run-CAR-T cell apoptosis and tumor necrosis factor (TNF) secretion.
  • Investigation of Runx3 binding to the TNF promoter to regulate gene transcription.

Main Results:

  • Run-CAR-T cells exhibited long-lasting antitumor activity and superior tumor control compared to conventional CAR-T cells.
  • Increased circulation and tumor accumulation of Run-CAR-T cells demonstrated enhanced in vivo persistence.
  • Run-CAR-T cells showed reduced cell death, enhanced proliferation, and effector functions within the tumor microenvironment.
  • In vitro studies confirmed decreased activation-induced cell death (AICD) and suppressed TNF secretion in Run-CAR-T cells.
  • Runx3 was found to directly suppress TNF gene transcription by binding to its promoter.

Conclusions:

  • Runx3 coexpression significantly enhances CAR-T cell persistence and antitumor efficacy in solid tumors.
  • Runx3-mediated suppression of TNF secretion contributes to improved CAR-T cell survival and function.
  • Runx3-engineered CAR-T cells represent a novel and promising therapeutic modality for solid tumor treatment.
Keywords:
AICDCAR-T therapyRunx3TNFhepatocellular carcinoma

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