Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling
Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling
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DOI：
10.1016/j.chembiol.2022.05.012
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发表时间：
2022-08-18
影响因子：
8.6
通讯作者：
Cang, Yong
中科院分区：
文献类型：
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作者：
Geng, Chen-Lu;Chen, Jun-Yi;Cang, Yong
程序性细胞死亡蛋白1 （PD-1）检查点阻断治疗需要CD28共刺激受体来促进CD8(+) T细胞扩增和细胞毒性。然而，在耗竭的T细胞和免疫衰老过程中，CD28的表达经常丢失，这限制了PD-1免疫治疗在癌症患者中的临床益处。在这里，使用一个小脑敲入小鼠模型，恢复体内T细胞对来那度胺（一种免疫调节亚胺药物）的反应，我们发现来那度胺在PD-1阻断后恢复了cd28缺陷CD8(+) T细胞的抗肿瘤活性。来那度胺重定向CRL4（Crbn）泛素连接酶降解T细胞中的Ikzf1和Ikzf3，并释放旁分泌白介素-2 （IL-2）和细胞内Notch信号，这些信号共同绕过CD28激活肿瘤内CD8+ T细胞和通过PD-1阻断抑制肿瘤生长的需要。我们的研究结果表明，PD-1免疫疗法可以从来那度胺联合治疗大量CD28- T细胞浸润的实体瘤中获益。
Programmed cell death protein 1 (PD-1) checkpoint blockade therapy requires the CD28 co-stimulatory re-ceptor for CD8(+) T cell expansion and cytotoxicity. However, CD28 expression is frequently lost in exhausted T cells and during immune senescence, limiting the clinical benefits of PD-1 immunotherapy in individuals with cancer. Here, using a cereblon knockin mouse model that regains in vivo T cell response to lenalidomide, an immunomodulatory imide drug, we show that lenalidomide reinstates the anti-tumor activity of CD28-defi-cient CD8(+) T cells after PD-1 blockade. Lenalidomide redirects the CRL4(Crbn) ubiquitin ligase to degrade Ikzf1 and Ikzf3 in T cells and unleashes paracrine interleukin-2 (IL-2) and intracellular Notch signaling, which collec-tively bypass the CD28 requirement for activation of intratumoral CD8+ T cells and inhibition of tumor growth by PD-1 blockade. Our results suggest that PD-1 immunotherapy can benefit from a lenalidomide combina-tion when treating solid tumors infiltrated with abundant CD28- T cells.