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Nat Commun:HRS磷酸化驱动PD-L1外泌体分泌并限制CD8+T细胞肿瘤浸润

2022-08-13 小药说药 小药说药

最新的研究表明,HRS的磷酸化对于CD8+T细胞的肿瘤浸润至关重要,并且这种作用主要由表达PD-L1的外泌体介导。

目前,使用PD-1/PD-L1抗体的免疫检查点阻断(ICB)治疗已证明对多种癌症有效,但是对ICB治疗具有响应的患者只占到了20-30%。最近的研究表明,具有高肿瘤内CD8+T细胞浸润的患者对ICB有更好的反应。为了提高免疫治疗的疗效,必须促进细胞毒性CD8+T细胞的肿瘤内迁移。然而,调节CD8+T细胞肿瘤浸润的分子机制尚不清楚。

外泌体是由细胞分泌的胞外囊泡(sEV),可能影响细胞间的通讯,其中外泌体中负载的异质性是外泌体多种功能的基础。阐明货物分拣到外泌体的机制是理解外泌体异质性及其功能的关键。转运必需内体分选复合物(ESCRT)系统在外泌体发生过程中起着重要作用。HRS(肝细胞生长因子调节的酪氨酸激酶底物)是ESCRT的关键组成部分,它介导初始负载识别和分选到多囊泡内体(MVE),然后将其输送到质膜进行外泌体分泌。

最近的研究发现,在细胞外信号调节激酶(ERK)磷酸化后,HRS在空间上阻止了CD8+T细胞浸润到黑色素瘤组织中。在机制上,磷酸化HRS与PD-L1发生强烈相互作用,并选择性地促进PD-L1负载到外泌体,从而阻断CD8+T细胞浸润。在各种小鼠模型中,组成性磷酸化HRS的表达导致对抗PD-1治疗的抵抗,而抑制HRS磷酸化可增强PD-1阻断的治疗效果。因此,抑制HRS磷酸化可能作为增强ICB治疗的潜在策略。

ERK对HRS的磷酸化限制了CD8+T细胞向肿瘤的浸润

使用特异性针对HRS磷酸化的抗体,能够在细胞中检测到磷酸化HRS。使用该抗体,在黑色素瘤患者样本的组织中检测HRS的磷酸化和CD8+T细胞的分布。结果显示,与低HRS磷酸化的肿瘤相比,高HRS磷酸化的肿瘤中的CD8+TIL水平较低。原发性黑色素瘤中CD8+TIL的数量与HRS磷酸化水平呈负相关(R=−0.4060; P<0.001)。

HRS磷酸化抑制TIL并诱导抗PD-1治疗的耐药性

CD8+T细胞浸润与抗肿瘤免疫有关。为了研究肿瘤细胞中的HRS磷酸化是否参与免疫抑制,研究建立了稳定的YUMMER1.7细胞系,表达野生型(“HRSWT”)、磷酸化缺陷型(“HRSS345A”)和磷酸化突变型(“HRSS345D”)。

随后在C57BL/6小鼠中,研究了HRS磷酸化是否影响YUMMER1.7肿瘤的PD-1阻断治疗。结果显示,抗PD-1抗体有效抑制表达HRSS345A肿瘤的生长,而PD-1阻断的抑制作用在HRSWT肿瘤中降低,在HRSS345D肿瘤中几乎消失。这些结果表明,由HRS磷酸化诱导的免疫抑制阻碍了PD-1阻断性抗体的效果,因此,抑制HRS磷酸化可能增强PD-1阻断剂的治疗效果。

HRS磷酸化导致PD-L1在外泌体中选择性富集

接下来,研究了HRS磷酸化调节T细胞浸润的机制。HRS是ESCRT复合物的关键组成部分,它介导PD-L1向MVE的富集,PD-L1可以从MVE转移到溶酶体进行降解,这对PD-L1表面表达至关重要;也可以作为PD-L1外泌体分泌到细胞外,有助于肿瘤的免疫抑制作用。

通过对不同HRS磷酸化水平的细胞进行荧光染色,可以发现,PD-L1水平在HRS磷酸化高水平的HRSS345D细胞分泌的EVs中增加。此外,免疫沉淀研究表明,PD-L1与HRSS345D有强相互作用,而这种相互作用在S345A突变型中减弱。

这些结果表明,ERK介导的HRS磷酸化促进PD-L1向MVE的募集并以外泌体分泌。

HRS磷酸化的sEV有效抑制CD8+T细胞浸润

输注来自B16F10细胞表达PD-L1的sEVWTsEVS345D可显著促进小鼠模型中的PD-L1-KO B16F10肿瘤生长,在Rag2/−小鼠的肿瘤中没有观察到这种作用。sEVWT和sEVS345D抑制了CD8+T细胞向PD-L1-KO B16F10肿瘤的浸润,这与表达不同HRS突变体肿瘤中的CD8+TIL分析一致。

小结

肿瘤浸润的细胞毒性T细胞与患者对ICB的反应密切相关。为了制定有效的新策略来改善患者响应,了解T细胞肿瘤浸润的分子机制至关重要。最新的研究表明,HRS的磷酸化对于CD8+T细胞的肿瘤浸润至关重要,并且这种作用主要由表达PD-L1的外泌体介导。HRS磷酸化在抗PD-1治疗的耐药性中起着至关重要的作用。开发针对HRS磷酸化的小分子药物可能会提高PD-1阻断剂的疗效。

参考文献:

1.HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+T-cell infiltration into tumors. Nat Commun. 2022; 13: 4078.

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    2023-02-16 gds2009
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    2023-04-30 liuli5079
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    2022-10-25 liye789132251
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    2022-08-23 gwc392
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    2022-08-06 smartjoy
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    2022-08-06 ysjykql
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