Mevalonate Blockade in Cancer Cells Triggers CLEC9A(+) Dendritic Cell-Mediated Antitumor Immunity
Mevalonate Blockade in Cancer Cells Triggers CLEC9A(+) Dendritic Cell-Mediated Antitumor Immunity
复制标题
癌细胞中的甲羟戊酸阻断触发 CLEC9A( ) 树突状细胞介导的抗肿瘤免疫
DOI：
10.1158/0008-5472.can-20-3977
复制
发表时间：
2021
期刊：
影响因子：
11.2
通讯作者：
Xia Xiaojun
中科院分区：
文献类型：
--
作者：
Xu Feifei;Wang Zining;Zhang Hongxia;Chen Jiemin;Wang Xiaojuan;Cui Lei;Xie Chunyuan;Li Mengyun;Wang Fang;Zhou Penghui;Liu Jinyun;Huang Peng;Xia Xiaodong;Xia Xiaojun
在癌细胞中经常观察到甲羟戊酸（MVA）代谢活性过高，阻断该途径会抑制肿瘤细胞脂质合成和细胞生长，并增强肿瘤免疫原性。然而，肿瘤细胞 MVA 代谢阻断如何促进抗肿瘤免疫反应仍不清楚。在这里，我们表明，抑制肿瘤细胞中的 MVA 代谢途径会引发 1 型经典树突状细胞 (cDC1) 介导的肿瘤识别和抗原交叉呈递，从而实现抗肿瘤免疫。从机制上讲，MVA 阻断破坏了小 GTPase Rac1 的异戊二烯化，并诱导癌细胞肌动蛋白丝暴露，这种暴露被 CLEC9A（一种在 cDC1 上特异性表达的 C-凝集素受体）识别，进而激活抗肿瘤 T 细胞。肿瘤细胞中的 MVA 通路阻断或 Rac1 敲低可在免疫活性小鼠中诱导 CD8+T 细胞介导的抗肿瘤免疫，但在缺乏 CLEC9A+ 树突状细胞的 Batf3−/− 小鼠中则不然。这些发现表明，肿瘤MVA代谢阻断通过CLEC9A介导的肿瘤细胞细胞骨架的免疫识别来刺激cDC1反应，说明了一种新的免疫监视机制，树突状细胞通过该机制监测肿瘤代谢失调，并深入了解MVA途径抑制如何增强抗癌免疫。意义这些发现表明，癌细胞中的甲羟戊酸阻断会破坏Rac1异戊二烯化，以增加传统树突状细胞的识别和交叉呈递，表明该轴作为癌症的潜在靶点免疫疗法。
Hyperactive mevalonate (MVA) metabolic activity is often observed in cancer cells, and blockade of this pathway inhibits tumor cell lipid synthesis and cell growth and enhances tumor immunogenicity. How tumor cell MVA metabolic blockade promotes antitumor immune responses, however, remains unclear. Here we show that inhibition of the MVA metabolic pathway in tumor cells elicits type 1 classical dendritic cells (cDC1)–mediated tumor recognition and antigen cross-presentation for antitumor immunity. Mechanistically, MVA blockade disrupted prenylation of the small GTPase Rac1 and induced cancer cell actin filament exposure, which was recognized by CLEC9A, a C-lectin receptor specifically expressed on cDC1s, in turn activating antitumor T cells. MVA pathway blockade or Rac1 knockdown in tumor cells induced CD8+T-cell-mediated antitumor immunity in immunocompetent mice but not inBatf3−/−mice lacking CLEC9A+dendritic cells. These findings demonstrate tumor MVA metabolic blockade stimulates a cDC1 response through CLEC9A-mediated immune recognition of tumor cell cytoskeleton, illustrating a new immune surveillance mechanism by which dendritic cells monitor tumor metabolic dysregulation and providing insight into how MVA pathway inhibition may potentiate anticancer immunity.SignificanceThese findings suggest that mevalonate blockade in cancer cells disrupts Rac1 prenylation to increase recognition and cross-presentation by conventional dendritic cells, suggesting this axis as a potential target for cancer immunotherapy.