Scholarlink

<p>CD8<sup>+</sup> T stem cell memory (T<sub>SCM</sub>) cells show clinical promise for cancer immunotherapy, but T<sub>SCM</sub> cell generation in clinical settings requires further optimization. Ponatinib is a tyrosine kinase inhibitor primarily targeting BCR-ABL1 and used for the treatment of chronic myeloid leukemia. Here, we investigate the effect of ponatinib on T cell activation and differentiation. Acting off-target, ponatinib inhibits LCK and PI3K signaling to enhance the transcriptional functions of <i>TCF7</i> and <i>FOXO1</i>, thereby promoting CD8<sup>+</sup> T<sub>SCM</sub> cell differentiation. Mechanistically, stable and sustained, but not intermittent, inhibition of the LCK and PI3K pathways is essential for CD8<sup>+</sup> T<sub>SCM</sub> cell induction. In mouse tumor models, ponatinib treatment exhibits antitumor efficacy alone and in combination with PD-1 blockade. Furthermore, ponatinib increases chimeric antigen receptor (CAR) T<sub>SCM</sub> cells by reducing CAR T cell exhaustion, resulting in durable antitumor efficacy. Our results thus implicate ponatinib as therapeutic immunomodulator, inducing T<sub>SCM</sub> cells for improved antitumor T cell activity.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Ponatinib inhibits LCK and PI3K signaling and promotes CD8+ T stem cell memory cell development

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月7日

查看全文
  • Yuki Okuhiro,
  • Sachiko Ito,
  • Keisuke Watanabe,
  • Yue Yan,
  • Kazuhiro Kumagai,
  • Takahiko Sato,
  • Yasuhiro Kojima,
  • Yuki Fujioka,
  • Naoto Takahashi,
  • Hitoshi Kiyoi,
  • Yuka Maeda,
  • Takuma Kato,
  • Hiroyoshi Nishikawa

摘要

CD8+ T stem cell memory (TSCM) cells show clinical promise for cancer immunotherapy, but TSCM cell generation in clinical settings requires further optimization. Ponatinib is a tyrosine kinase inhibitor primarily targeting BCR-ABL1 and used for the treatment of chronic myeloid leukemia. Here, we investigate the effect of ponatinib on T cell activation and differentiation. Acting off-target, ponatinib inhibits LCK and PI3K signaling to enhance the transcriptional functions of TCF7 and FOXO1, thereby promoting CD8+ TSCM cell differentiation. Mechanistically, stable and sustained, but not intermittent, inhibition of the LCK and PI3K pathways is essential for CD8+ TSCM cell induction. In mouse tumor models, ponatinib treatment exhibits antitumor efficacy alone and in combination with PD-1 blockade. Furthermore, ponatinib increases chimeric antigen receptor (CAR) TSCM cells by reducing CAR T cell exhaustion, resulting in durable antitumor efficacy. Our results thus implicate ponatinib as therapeutic immunomodulator, inducing TSCM cells for improved antitumor T cell activity.