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TIPE2 deletion improves the therapeutic potential of adoptively transferred NK cells

Jiacheng Bi1, Chen Huang2, Xiaomeng Jin2

  • 1The CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People's Republic of China haoyusun@ustc.edu.cn jc.bi@siat.ac.cn tzg@ustc.edu.cn.

Journal for Immunotherapy of Cancer
|February 1, 2023
PubMed
Abstract

Insights

Targeting TIPE2 enhances natural killer (NK) cell therapy for solid tumors by preventing exhaustion in the tumor microenvironment (TME). Deleting TIPE2 boosts NK cell antitumor activity and infiltration, offering a promising therapeutic strategy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cell Therapy

Background:

  • Adoptive natural killer (NK) cell therapy shows promise for solid tumors but is limited by NK cell exhaustion within the tumor microenvironment (TME).
  • The specific molecular checkpoint driving NK cell exhaustion in the TME has not been clearly identified.

Purpose of the Study:

  • To investigate the role of TIPE2 as a molecular checkpoint in NK cell exhaustion within the TME.
  • To evaluate the therapeutic potential of targeting TIPE2 to enhance NK cell-based cancer immunotherapy.

Main Methods:

  • Single-cell transcriptomic analysis and gene reporter mice were used to correlate TIPE2 expression with NK cell exhaustion in human and mouse TME.
  • NK cell therapy efficacy was assessed using TIPE2-deficient mouse, peripheral blood-derived human, and induced pluripotent stem cell (iPSC)-derived human NK cells.
  • CRISPR/Cas9 technology was employed for TIPE2 deletion in human NK cells.
  • The synergistic effects of deleting TIPE2 and CISH (another checkpoint molecule) were investigated.

Main Results:

  • TIPE2 expression positively correlated with NK cell exhaustion in the TME of both humans and mice.
  • High TIPE2 expression in NK cells was associated with poorer patient survival.
  • TIPE2 deletion significantly enhanced the antitumor activity of adoptively transferred NK cells (mouse, human peripheral blood, and iPSC-derived).
  • TIPE2-deleted NK cells exhibited improved tumor infiltration and effector functions.
  • Combined deletion of TIPE2 and CISH demonstrated synergistic enhancement of antitumor activity in vivo.

Conclusions:

  • TIPE2 acts as a critical molecular checkpoint regulating NK cell function and exhaustion in the TME.
  • Targeting TIPE2 represents a promising strategy to overcome NK cell exhaustion and improve adoptive NK cell therapy efficacy against solid tumors.
  • The combined targeting of TIPE2 and CISH may offer enhanced therapeutic benefits.
Keywords:
immunotherapy, adoptivekiller cells, natural

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