Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer.
Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer.
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DOI：
10.1136/jitc-2021-002474
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发表时间：
2021-07
影响因子：
10.9
通讯作者：
Kim IS
中科院分区：
文献类型：
--
作者：
Nam GH;Kwon M;Jung H;Ko E;Kim SA;Choi Y;Song SJ;Kim S;Lee Y;Kim GB;Han J;Woo J;Cho Y;Jeong C;Park SY;Roberts TM;Cho YB;Kim IS
他汀类药物优先促进肿瘤特异性细胞凋亡，通过消耗类异戊二烯，如焦磷酸法呢酯和焦磷酸香叶基香叶基。然而，他汀类药物尚未被批准用于临床癌症治疗，部分原因是对他汀类药物敏感性的分子决定因素了解不足。在这里，我们研究了他汀类药物引起KRAS突变（KRASmut）肿瘤免疫原性增强的潜力。免疫印迹法、流式细胞术和共聚焦显微镜检测细胞免疫原性。在KRASmut肿瘤模型中评估了使用他汀类药物的单一或联合治疗的免疫抑制功效，包括同基因结肠直肠癌和基因工程肺和胰腺肿瘤。使用NanoString分析，我们分析了他汀类药物如何影响体内树突状细胞抗原呈递相关的基因特征，并评估了他汀类药物是否可以诱导CD 8 + T细胞免疫。进行多重免疫组织化学以更好地了解复杂的肿瘤免疫微环境。他汀类药物介导的KRAS异戊烯化抑制通过减弱KRAS突变的抗内质网（ER）应激作用引起严重的ER应激，从而导致KRASmut癌细胞的免疫原性细胞死亡（ICD）。此外，他汀类药物介导的ICD增强了树突状细胞的交叉致敏能力，从而激发了针对KRASmut肿瘤的CD 8 + T细胞免疫应答。使用他汀类药物和奥沙利铂（ICD诱导剂）的联合治疗显著增强了KRASmut肿瘤的免疫原性，并促进了同基因和基因工程KRASmut肿瘤模型中的肿瘤特异性免疫。沿着免疫检查点抑制剂，上述联合疗法克服了对PD-1阻断疗法的抗性，提高了KRASmut肿瘤模型的存活率。我们的研究结果表明，KRAS突变可能是他汀类药物引发有效的肿瘤特异性免疫的分子靶点。
Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors. The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment. Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models. Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.
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