Overcoming vaccine-associated hypoxia with advanced biomaterials to enhance cancer immunotherapy

项目摘要 克服肿瘤细胞疫苗的不良效果将需要增强免疫系统的激活和 防止免疫抑制的肿瘤微环境，如局部缺氧。在这项提案中，我们将 通过使用先进的释氧生物材料(O2- 冷冻剂)对抗低氧诱导的免疫抑制，并改善相关的抗肿瘤免疫反应 前列腺癌的小鼠模型。我们在小鼠身上的初步数据表明：(I)O2-冷冻剂可以逆转局部 低氧和恢复关键免疫细胞(树突状细胞；树突状细胞)的功能；(2)一旦进入体内，冷冻疫苗 有效地定位移植的肿瘤细胞，可控地释放免疫调节因子，并招募大量 来自宿主的DC的数量；以及(Iii)诱导特异性和强效疫苗诱导的T细胞介导的抗肿瘤 豁免权。在这里，我们将优化O2-冷冻剂的特性，以实现最大的抗肿瘤效果和安全性； 并评估他们抑制局部低氧应激和改善DC招募、激活和归巢的能力 到引流的淋巴结处。最后，我们将在预防性和治疗性小鼠身上测试O2-冷冻胶疫苗 前列腺癌模型以确定其诱导特异、有效和持久的抗肿瘤作用的能力 免疫反应。这项提议可能会对该领域产生持续的影响，因为它定义了一种新的癌症途径 独立运作但与其他疗法协同的免疫疗法。

Project Summary Overcoming the poor efficacy of tumor cell vaccines will require enhancing activation of the immune system and preventing an immunosuppressive tumor microenvironment such as local hypoxia. In this proposal, we will address this critical need by engineering tumor cell vaccines with advanced oxygen-releasing biomaterials (O2- cryogels) to combat hypoxia-driven immunosuppression and improve antitumor immune responses in relevant mouse models of prostate cancer. Our preliminary data in mice indicate that: (i) O2-cryogels can reverse local hypoxia and restore the function of key immune cells (dendritic cells; DCs); (ii) once in the body, cryogel vaccines efficiently localize transplanted tumor cells, controllably release immunomodulatory factors, and recruit large numbers of DCs from the host; and (iii) elicit a specific and robust vaccine-induced T cell-mediated antitumor immunity. Here, we will optimize the characteristics of O2-cryogels for maximum antitumor efficacy and safety; and assess their ability to suppress the local hypoxic stress and improve DC recruitment, activation, and homing to the draining lymph nodes. Finally, we will test O2-cryogel vaccines in prophylactic and therapeutic mouse models of prostate cancer to determine their ability to induce specific, effective, and long-lasting antitumor immune responses. This proposal may have a sustained impact on the field by defining a new avenue of cancer immunotherapy that operates independently but synergizes with other therapies.