Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.
Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.
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甲磺酸伊马替尼靶向胃肠道间质瘤（GIST）中突变的KIT癌蛋白，并在80%的患者中获得临床应答。该机制被认为主要依赖于抑制肿瘤细胞存活和增殖的KIT驱动信号。使用自发性GIST的小鼠模型，我们发现免疫系统对伊马替尼的抗肿瘤作用有很大贡献。伊马替尼疗法通过降低免疫抑制酶吲哚胺2，3-双加氧酶（Ido）的肿瘤细胞表达来激活CD 8 + T细胞并诱导肿瘤内的调节性T细胞（T reg）凋亡。同时免疫治疗增强了伊马替尼在小鼠GIST中的疗效。在新鲜获得的人GIST标本中，T细胞谱与伊马替尼敏感性和IDO表达相关。因此，T细胞对于伊马替尼在GIST中的抗肿瘤作用至关重要，并且伴随的免疫治疗可以进一步改善用靶向药物治疗的人类癌症的结果。
Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and achieves a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the anti-tumor effects of imatinib. Imatinib therapy activated CD8+ T cells and induced regulatory T cell (T reg) apoptosis within the tumor by reducing tumor cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are critical to the anti-tumor effects of imatinib in GIST and concomitant immunotherapy may further improve outcome in human cancers treated with targeted agents.