TYRO3 通过限制固有免疫和肿瘤铁死亡来诱导抗 PD-1/PD-L1 治疗耐药性。
TYRO3 induces anti-PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis.
机构信息
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA.
出版信息
J Clin Invest. 2021 Apr 15;131(8). doi: 10.1172/JCI139434.
Immune checkpoint blockade therapy has demonstrated promising clinical outcomes for multiple cancer types. However, the emergence of resistance as well as inadequate biomarkers for patient stratification have largely limited the clinical benefits. Here, we showed that tumors with high TYRO3 expression exhibited anti-programmed cell death protein 1/programmed death ligand 1 (anti-PD-1/PD-L1) resistance in a syngeneic mouse model and in patients who received anti-PD-1/PD-L1 therapy. Mechanistically, TYRO3 inhibited tumor cell ferroptosis triggered by anti-PD-1/PD-L1 and facilitated the development of a protumor microenvironment by reducing the M1/M2 macrophage ratio, resulting in resistance to anti-PD-1/PD-L1 therapy. Inhibition of TYRO3 promoted tumor ferroptosis and sensitized resistant tumors to anti-PD-1 therapy. Collectively, our findings suggest that TYRO3 could serve as a predictive biomarker for patient selection and a promising therapeutic target to overcome anti-PD-1/PD-L1 resistance.
免疫检查点阻断疗法在多种癌症类型中显示出了有前景的临床结果。然而，耐药性的出现以及缺乏患者分层的生物标志物在很大程度上限制了其临床获益。在这里，我们发现在同种异体小鼠模型和接受抗 PD-1/PD-L1 治疗的患者中，高 TYRO3 表达的肿瘤表现出抗程序性细胞死亡蛋白 1/程序性死亡配体 1（抗 PD-1/PD-L1）耐药性。在机制上，TYRO3 抑制了抗 PD-1/PD-L1 触发的肿瘤细胞铁死亡，并通过降低 M1/M2 巨噬细胞比例促进了促肿瘤微环境的发展，导致对抗 PD-1/PD-L1 治疗的耐药性。TYRO3 的抑制促进了肿瘤的铁死亡，并使耐药肿瘤对抗 PD-1 治疗敏感。总的来说，我们的研究结果表明，TYRO3 可以作为预测生物标志物来选择患者，并作为一种有前途的治疗靶点来克服抗 PD-1/PD-L1 耐药性。
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