A lung cancer vaccine based on exosomes of induced pluripotent stem cells

一种基于诱导多能干细胞外体的肺癌疫苗 摘要 肺癌研究中的一个关键挑战是开发预防肺癌的创新疫苗。 恶毒。最近开发肺癌疫苗的努力在很大程度上失败了，可能是因为他们专注于 诱导针对单个肺肿瘤相关抗原的免疫反应。如果肺癌疫苗针对的是 多种抗原只存在于肺肿瘤中，而不存在于正常成人组织中，成功的机会将是 有很大的进步。诱导多能干细胞(IPSCs)是由体细胞重新编程而来，具有 自我更新和发育成成人身体的所有细胞类型的能力。已知IPSCs与肿瘤 细胞共享正常成人组织中不存在的癌胚抗原。肺肿瘤还含有一种 具有高致瘤性和自我更新能力的肿瘤启动细胞(TIC)亚群 对传统疗法的抵抗力。利用肿瘤细胞和IPSCs之间的抗原性相似性， 我们建议彻底研究一种由小鼠外切体组成的肺癌疫苗的疗效。 表达粒细胞巨噬细胞集落刺激因子的IPSCs作为免疫刺激因子 佐剂(IPSC-exo)。我们假设IPSC-exo疫苗通过触发 CD8+T细胞依赖的免疫反应和消除肺部抽搐。在这笔拨款中，我们将调查这一点 两种临床相关、免疫活性的小鼠肺癌模型的假说。两个具体目标是 建议：1)研究IPSC-exo疫苗对肺癌的翻译潜力；2)阐明 IPSC-exo疫苗预防肺癌的机制。我们相信，建议的成功 实验将导致针对人类肺部恶性肿瘤的类似疫苗的临床试验。

A lung cancer vaccine based on exosomes of induced pluripotent stem cells ABSTRACT A critical challenge in lung cancer research is to develop innovative vaccines to protect against pulmonary malignancy. Recent efforts to develop lung cancer vaccines have largely failed, probably due to their focus on inducing immune responses against individual lung tumor-associated antigens. If a lung cancer vaccine targets multiple antigens present only in lung tumors, but not in normal adult tissues, the chance of success will be greatly improved. Induced pluripotent stem cells (iPSCs) are reprogrammed from somatic cells and have the capacity of self-renewing and developing into all cell types of the adult body. It is known that iPSCs and tumor cells share carcinoembryonic antigens that are absent in normal adult tissues. Lung tumors also contain a subpopulation of tumor-initiating cells (TICs) with high tumorigenicity and self-renewal capability that contribute to the resistance to conventional therapies. Exploiting the antigenic similarity between tumor cells and iPSCs, we propose to thoroughly investigate efficacy of a lung cancer vaccine composed of exosomes from murine iPSCs expressing granulocyte-macrophage colony stimulating factor (GM-CSF) as an immunostimulatory adjuvant (iPSC-exo). We hypothesize that iPSC-exo vaccination prevents lung tumorigenesis by triggering CD8+ T cell-dependent immune responses and eradicating lung TICs. In this grant, we will investigate this hypothesis in two clinically relevant, immunocompetent murine lung tumor models. Two specific aims are proposed: 1) Investigate the translational potential of iPSC-exo vaccination against lung cancer; 2) Elucidate the mechanism by which iPSC-exo vaccination prevents lung cancer. We believe that the success of proposed experiments will lead to clinical trials of a similar vaccine against human pulmonary malignancy.