2026-06-09 国立がん研究センター,名古屋大学,京都大学,秋田大学
◆研究では、ポナチニブがT細胞活性化の起点であるLCKとPI3Kシグナルを強力かつ持続的に抑制し、代謝を解糖系から酸化的リン酸化へ転換させることでTSCM細胞への分化を促進することを解明した。マウス腫瘍モデルでは腫瘍縮小効果が確認され、抗PD-1抗体との併用で効果はさらに増強した。また、CAR-T細胞作製時や治療後の投与でもTSCM様細胞が増加し、白血病および固形がんモデルで抗腫瘍活性が向上した。さらに、ポナチニブ投与中の慢性骨髄性白血病患者でもTSCM細胞の増加が確認され、既存薬を利用した新たながん免疫療法戦略として期待される。
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＜関連情報＞
- https://www.ncc.go.jp/jp/information/pr_release/2026/0609/index.html
- https://www.nature.com/articles/s41467-026-71375-2
ポナチニブはLCKおよびPI3Kシグナル伝達を阻害し、CD8 + T幹細胞記憶細胞の発達を促進する Ponatinib inhibits LCK and PI3K signaling and promotes CD8+ T stem cell memory cell development
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
Nature Communications Published:07 April 2026
DOI:https://doi.org/10.1038/s41467-026-71375-2
Abstract
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.
