Disulfiram bolsters T‐cell anti‐tumor immunity through direct activation of LCK‐mediated TCR signaling
Disulfiram bolsters T‐cell anti‐tumor immunity through direct activation of LCK‐mediated TCR signaling
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DOI：
10.15252/embj.2022110636
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发表时间：
2022-05
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影响因子：
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通讯作者：
Qinlan Wang;Tingfang Zhu;Nai-fa Miao;Yingying Qu;Zhuning Wang;Yi-Wei Chao;Jing Wang;Wei Wu;Xinyi Xu;Chenqi Xu;Lina Xia;Feng Wang
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作者：
Qinlan Wang;Tingfang Zhu;Nai-fa Miao;Yingying Qu;Zhuning Wang;Yi-Wei Chao;Jing Wang;Wei Wu;Xinyi Xu;Chenqi Xu;Lina Xia;Feng Wang
T细胞抗原受体（TCR）-CD 3复合物的活化对于诱导CD 8 + T细胞的抗肿瘤应答至关重要。在这里，我们发现双硫仑（DSF），一种FDA批准的药物，以前用于治疗酒精依赖，直接激活TCR信号。从机制上讲，DSF共价结合淋巴细胞特异性蛋白酪氨酸激酶（LCK）的Cys 20/Cys 23残基，并增强其酪氨酸394磷酸化，从而促进LCK激酶活性并增强效应T细胞功能、白细胞介素-2产生、代谢重编程和增殖。此外，我们的体内数据显示，DSF通过激活CD 8 + T细胞促进小鼠对黑色素瘤和结肠癌的抗肿瘤免疫，并且这种作用通过抗PD-1共治疗增强。我们的结论是，DSF直接激活LCK介导的TCR信号传导，诱导强大的抗肿瘤免疫，为DSF对癌症的治疗作用提供了新的分子见解。
Activation of the T‐cell antigen receptor (TCR)–CD3 complex is critical to induce the anti‐tumor response of CD8+ T cells. Here, we found that disulfiram (DSF), an FDA‐approved drug previously used to treat alcohol dependency, directly activates TCR signaling. Mechanistically, DSF covalently binds to Cys20/Cys23 residues of lymphocyte‐specific protein tyrosine kinase (LCK) and enhances its tyrosine 394 phosphorylation, thereby promoting LCK kinase activity and boosting effector T cell function, interleukin‐2 production, metabolic reprogramming, and proliferation. Furthermore, our in vivo data revealed that DSF promotes anti‐tumor immunity against both melanoma and colon cancer in mice by activating CD8+ T cells, and this effect was enhanced by anti‐PD‐1 co‐treatment. We conclude that DSF directly activates LCK‐mediated TCR signaling to induce strong anti‐tumor immunity, providing novel molecular insights into the therapeutic effect of DSF on cancer.