Journal for immunotherapy of cancer · 2026
KLF4 overexpression in CAR T cells enhances antitumor potency by preventing exhaustion.
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Wang Haoqi, Meng Xianglong, Feng Yuanyuan, Su Anqi, Qin Wentao, Shen Junjie, Lu Kunyu, Gu Lingling, Ma Yujie, Wang Yaxing, Mao Yuqing, Ji Dongdong, Zong Lu, Zheng Meijuan, Du Yingying, Cong Jingjing, Li Jing, Wang Xuefu
Аннотация
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for patients with refractory or relapsed lymphoma or leukemia. However, inefficient activity and insufficient persistence of CAR T cells impede the durability of its therapeutic efficacy.
METHODS: Krüppel-like factor 4 (KLF4)-overexpressing CAR T cells were generated and assessed for function, exhaustion, and transcriptional changes using in vitro stimulation models and RNA sequencing, with antitumor efficacy validated in mouse models.
RESULTS: We report that KLF4 overexpression enhances the durability of CAR T-cell antitumor efficacy. KLF4 overexpression enhanced CAR T-cell activity and promoted the differentiation into effector CAR T cells. Furthermore, KLF4 overexpression prevented CAR T-cell exhaustion induced by continuous tumor antigen stimulation. RNA sequencing data confirmed that KLF4 overexpression led to the upregulation of genes involved in effector functions and the downregulation of genes associated with exhaustion in CAR T cells. Notably, KLF4-overexpressing CAR T cells delayed tumor growth, prolonged the survival of mice with hematological malignancies, and exhibited reduced exhaustion and enhanced effector functions in vivo relative to normal CAR T cells.
CONCLUSIONS: Our findings highlight the potential of KLF4 overexpression as a therapeutic approach to counteract CAR T-cell exhaustion and enhance antitumor activity, underscoring its therapeutic promise in clinical immunotherapy.
METHODS: Krüppel-like factor 4 (KLF4)-overexpressing CAR T cells were generated and assessed for function, exhaustion, and transcriptional changes using in vitro stimulation models and RNA sequencing, with antitumor efficacy validated in mouse models.
RESULTS: We report that KLF4 overexpression enhances the durability of CAR T-cell antitumor efficacy. KLF4 overexpression enhanced CAR T-cell activity and promoted the differentiation into effector CAR T cells. Furthermore, KLF4 overexpression prevented CAR T-cell exhaustion induced by continuous tumor antigen stimulation. RNA sequencing data confirmed that KLF4 overexpression led to the upregulation of genes involved in effector functions and the downregulation of genes associated with exhaustion in CAR T cells. Notably, KLF4-overexpressing CAR T cells delayed tumor growth, prolonged the survival of mice with hematological malignancies, and exhibited reduced exhaustion and enhanced effector functions in vivo relative to normal CAR T cells.
CONCLUSIONS: Our findings highlight the potential of KLF4 overexpression as a therapeutic approach to counteract CAR T-cell exhaustion and enhance antitumor activity, underscoring its therapeutic promise in clinical immunotherapy.