Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses Against Hepatocellular Carcinoma.
Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses Against Hepatocellular Carcinoma.
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冷诱导RNA结合蛋白作为疫苗平台增强对肝细胞癌的免疫应答。
DOI：
10.3390/cancers12113397
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发表时间：
2020-11-16
期刊：
影响因子：
5.2
通讯作者：
Sarobe P
中科院分区：
文献类型：
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作者：
Silva L;Egea J;Villanueva L;Ruiz M;Llopiz D;Repáraz D;Aparicio B;Lasarte-Cia A;Lasarte JJ;Ruiz de Galarreta M;Lujambio A;Sangro B;Sarobe P
目前基于免疫抑制元件的阻断的免疫疗法在肝癌患者中提供有限的结果。在这里，我们测试了这种疗法与基于冷诱导RNA结合蛋白（CIRP）的疫苗的组合是否会提高其疗效。免疫疗法与基于CIRP的疫苗的组合增加了疫苗的免疫原性，并且当在几种肝癌小鼠模型中进行测试时，产生了更好的治疗效果。尽管在外周器官中观察到良好的免疫应答，但浸润肿瘤的淋巴细胞似乎耗尽，功能能力较弱。最后，通过使用相同的策略，我们制备了一种新的基于CIRP的疫苗，该疫苗含有磷脂酰肌醇蛋白聚糖-3，这是肝癌患者中常见的人类抗原。包含这种新疫苗的等效组合也具有高度免疫原性。这表明基于CIRP的疫苗可以增强当前免疫疗法提供的有益效果。然而，他们也应该考虑加入新的元素，以克服在肿瘤淋巴细胞中观察到的局限性。基于免疫检查点抑制剂（ICPI）的治疗在肝细胞癌（HCC）患者中产生了有希望的结果，尽管结果有限。已提议将疫苗作为联合伙伴，以提高对免疫接种疫苗倡议的反应率。因此，我们分析了基于TLR 4配体冷诱导RNA结合蛋白（CIRP）加ICPI的疫苗的联合作用。用含有与CIRP连接的卵清蛋白（OVA-CIRP）的疫苗（有或没有ICPI）免疫小鼠，并在皮下和原位肝癌小鼠模型中测试抗原特异性应答和治疗功效。OVA-CIRP引发多表位T细胞应答，当与ICPI（抗PD-1和抗CTLA-4）组合时，其进一步增强。当在皮下和肝内B16-OVA肿瘤以及原位PM299 L HCC模型中测试时，OVA-CIRP与ICPI的组合增强了ICPI诱导的治疗反应。这种效应与外周中较高的OVA特异性T细胞应答相关，尽管许多肿瘤浸润淋巴细胞仍显示衰竭表型。最后，含有与CIRP连接的人磷脂酰肌醇蛋白聚糖-3（GPC 3-CIRP）的新疫苗在人源化HLA-A2.01转基因小鼠中诱导明显的应答，其在与ICPI组合时增加。因此，基于CIRP的疫苗可能产生抗肿瘤免疫力，以增强HCC中的ICPI功效，尽管还应考虑阻断其他检查点分子和免疫抑制靶点。
Current immunotherapies based on blockade of immunosuppressive elements provide limited results in liver cancer patients. Here we tested whether combination of this therapy with a vaccine based on the Cold-Inducible RNA Binding Protein (CIRP) would improve its efficacy. Combination of immunotherapy with a CIRP-based vaccine increased vaccine immunogenicity and, when tested in several mouse models of liver cancer, resulted in better therapeutic effects. Despite good immune responses observed in peripheral organs, lymphocytes infiltrating the tumor appeared exhausted, with a weak functional capacity. Finally, by using the same strategy, we prepared a new CIRP-based vaccine containing glypican-3, human antigen commonly found in patients with liver cancer. An equivalent combination enclosing this new vaccine was also highly immunogenic. This suggests that CIRP-based vaccines may enhance the beneficial effects provided by current immunotherapies. However, they should also consider incorporating new elements to overcome limitations observed in tumor lymphocytes. Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the TLR4 ligand cold-inducible RNA binding protein (CIRP) plus ICPI. Mice were immunized with vaccines containing ovalbumin linked to CIRP (OVA-CIRP), with or without ICPI, and antigen-specific responses and therapeutic efficacy were tested in subcutaneous and orthotopic mouse models of liver cancer. OVA-CIRP elicited polyepitopic T-cell responses, which were further enhanced when combined with ICPI (anti-PD-1 and anti-CTLA-4). Combination of OVA-CIRP with ICPI enhanced ICPI-induced therapeutic responses when tested in subcutaneous and intrahepatic B16-OVA tumors, as well as in the orthotopic PM299L HCC model. This effect was associated with higher OVA-specific T-cell responses in the periphery, although many tumor-infiltrating lymphocytes still displayed an exhausted phenotype. Finally, a new vaccine containing human glypican-3 linked to CIRP (GPC3-CIRP) induced clear responses in humanized HLA-A2.01 transgenic mice, which increased upon combination with ICPI. Therefore, CIRP-based vaccines may generate anti-tumor immunity to enhance ICPI efficacy in HCC, although blockade of additional checkpoint molecules and immunosuppressive targets should be also considered.
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影响因子：
25.7
作者：
Sangro B;Chan SL;Meyer T;Reig M;El-Khoueiry A;Galle PR
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