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

基于诱导多能干细胞外泌体的肺癌疫苗 摘要 肺癌研究的一个关键挑战是开发创新疫苗， 恶性肿瘤最近开发肺癌疫苗的努力在很大程度上失败了，可能是由于他们专注于 诱导针对单个肺肿瘤相关抗原的免疫应答。如果肺癌疫苗针对 多个抗原仅存在于肺肿瘤中，而不存在于正常成人组织中，成功的机会将是 大大改善。诱导多能干细胞（iPSC）是从体细胞重编程而来的， 自我更新和发育成成人身体的所有细胞类型的能力。众所周知，iPSC和肿瘤 细胞共享癌胚抗原，而这些抗原在正常成人组织中是不存在的。肺肿瘤还含有 具有高致瘤性和自我更新能力的肿瘤起始细胞（TIC）亚群， 对传统疗法的抵抗。利用肿瘤细胞和iPSC之间的抗原相似性， 我们建议彻底研究由来自小鼠的外来体组成的肺癌疫苗的功效， 表达粒细胞-巨噬细胞集落刺激因子（GM-CSF）作为免疫刺激因子的iPSC 佐剂（iPSC-exo）。我们假设iPSC-exo疫苗接种通过触发肺肿瘤的发生来预防肺肿瘤的发生。 CD 8 + T细胞依赖性免疫应答和根除肺TIC。在这次拨款中，我们将对此进行调查 在两个临床相关的免疫活性鼠肺肿瘤模型中的假设。两个具体目标是 建议：1）研究iPSC-exo疫苗接种对肺癌的翻译潜力; 2）阐明 iPSC-exo疫苗接种预防肺癌的机制。我们认为，成功的建议， 这些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.