A therapeutically effective cancer vaccine must generate potent antitumor immune responses and be able to overcome tolerance mechanisms mediated by the progressing tumor itself. Previous studies showed that glycoprotein 100 (gp100), tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2) are promising immunogens for melanoma immunotherapy. In this study, we administered these three melanoma-associated antigens via lentiviral vectors (termed LV-3Ag) and found that this multi-antigen vaccine strategy markedly increased functional T-cell infiltration into tumors and generated protective and therapeutic antitumor immunity. We also engineered a novel immunotoxin, αFAP-PE38, capable of targeting fibroblast activation protein (FAP)-expressing fibroblasts within the tumor stroma. When combined with αFAP-PE38, LV-3Ag exhibited greatly enhanced antitumor effects on tumor growth in an established B16 melanoma model. The mechanism of action underlying this combination treatment likely modulates the immune suppressive tumor microenvironment and, consequently, activates cytotoxic CD8(+) T cells capable of specifically recognizing and destroying tumor cells. Taken together, these results provide a strong rationale for combining an immunotoxin with cancer vaccines for the treatment of patients with advanced cancer.

中文翻译：

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一种多抗原疫苗，结合靶向肿瘤相关成纤维细胞的免疫毒素，可治疗鼠类黑色素瘤。

治疗有效的癌症疫苗必须产生有效的抗肿瘤免疫应答，并能够克服由进展中的肿瘤本身介导的耐受机制。先前的研究表明，糖蛋白100（gp100），酪氨酸酶相关蛋白1（TRP1）和酪氨酸酶相关蛋白2（TRP2）是用于黑素瘤免疫治疗的有希望的免疫原。在这项研究中，我们通过慢病毒载体（称为LV-3Ag）施用了这三种与黑色素瘤相关的抗原，并发现这种多抗原疫苗策略显着增加了功能性T细胞对肿瘤的浸润并产生了保护性和治疗性抗肿瘤免疫力。我们还设计了一种新型免疫毒素αFAP-PE38，能够靶向肿瘤基质内表达成纤维细胞活化蛋白（FAP）的成纤维细胞。当与αFAP-PE38结合使用时，在已建立的B16黑色素瘤模型中，LV-3Ag对肿瘤生长表现出极大的抗肿瘤作用。这种联合治疗的潜在作用机制可能会调节免疫抑制性肿瘤微环境，并因此激活能够特异性识别和破坏肿瘤细胞的细胞毒性CD8（+）T细胞。综上所述，这些结果为将免疫毒素与癌症疫苗结合用于治疗晚期癌症患者提供了强有力的理由。