肿瘤细胞治疗研究
英文原题：Ponatinib inhibits LCK and PI3K signaling and promotes CD8(+) T stem cell memory cell development.
CD8+ T干细胞记忆（T SCM）细胞在癌症免疫治疗中显示出临床前景，但临床环境中T SCM细胞的生成需要进一步优化。
CD8+ T干细胞记忆（T SCM）细胞在癌症免疫治疗中显示出临床前景，但T SCM细胞在临床环境中的生成需要进一步优化。Ponatinib是一种主要靶向BCR-ABL1的酪氨酸激酶抑制剂，用于治疗慢性髓性白血病。在此，我们研究ponatinib对T细胞激活和分化的影响。通过脱靶作用，ponatinib抑制LCK和PI3K信号传导，增强TCF7和FOXO1的转录功能，从而促进CD8+ T SCM细胞分化。在机制上，稳定且持续而非间歇性地抑制LCK和PI3K通路对于CD8+ T SCM细胞诱导至关重要。在小鼠肿瘤模型中，ponatinib治疗单独以及与PD-1阻断联合均表现出抗肿瘤疗效。此外，ponatinib通过减少CAR T细胞耗竭来增加嵌合抗原受体（CAR）T SCM细胞，从而产生持久的抗肿瘤疗效。因此，我们的结果表明ponatinib可作为治疗性免疫调节剂，诱导T SCM细胞以改善抗肿瘤T细胞活性。
CD8 + T stem cell memory (T SCM ) cells show clinical promise for cancer immunotherapy, but T SCM 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 + T SCM cell differentiation. Mechanistically, stable and sustained, but not intermittent, inhibition of the LCK and PI3K pathways is essential for CD8 + T SCM 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 SCM cells by reducing CAR T cell exhaustion, resulting in durable antitumor efficacy. Our results thus implicate ponatinib as therapeutic immunomodulator, inducing T SCM cells for improved antitumor T cell activity.
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