State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Sci Adv. 2024 Nov;10(44):eadp0631. doi: 10.1126/sciadv.adp0631. Epub 2024 Nov 1.
Increasing evidence highlights the importance of immune mechanoregulation in establishing and sustaining tumor-specific cytotoxicity required for desirable immunotherapeutic outcomes. However, the molecular connections between mechanobiological inputs and outputs and the designated immune activities remain largely unclear. Here, we show that partial inhibition of non-muscle myosin II (NM II) augmented the traction force exerted by T cells and potentiated T cell cytotoxicity against tumors. By using T cells from mice and patients with cancer, we found that NM II is required for the activity of NKX3-2 in maintaining the expression of ADGRB3, which shapes the filamentous actin (F-actin) organization and ultimately attributes to the reduced traction force of T cells in the tumor microenvironment. In animal models, suppressing the NM II-NKX3-2-ADGRB3 pathway in T cells effectively suppressed tumor growth and improved the efficacy of the checkpoint-specific immunotherapy. Overall, this work provides insights into the biomechanical regulation of T cell cytotoxicity that can be exploited to optimize clinical immunotherapies.
越来越多的证据强调了免疫力学调节在建立和维持肿瘤特异性细胞毒性方面的重要性，而肿瘤特异性细胞毒性是免疫治疗效果所必需的。然而，力学输入和输出与指定免疫活动之间的分子联系在很大程度上仍不清楚。在这里，我们表明，非肌肉肌球蛋白 II（NM II）的部分抑制增强了 T 细胞施加的牵引力，并增强了 T 细胞对肿瘤的细胞毒性。通过使用来自患有癌症的小鼠和患者的 T 细胞，我们发现 NM II 对于 NKX3-2 维持 ADGRB3 的表达的活性是必需的，ADGRB3 塑造了丝状肌动蛋白（F-actin）的组织，最终导致 T 细胞在肿瘤微环境中的牵引力降低。在动物模型中，抑制 T 细胞中的 NM II-NKX3-2-ADGRB3 途径可有效抑制肿瘤生长，并提高检查点特异性免疫疗法的疗效。总的来说，这项工作为 T 细胞细胞毒性的生物力学调节提供了新的见解，可以用来优化临床免疫疗法。
