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功效将需要增强免疫系统的激活， 防止免疫抑制性肿瘤微环境如局部缺氧。在本提案中，我们将 通过用先进的释氧生物材料（O2- 冷冻凝胶）以对抗缺氧驱动的免疫抑制并改善相关的抗肿瘤免疫应答。 前列腺癌的小鼠模型。我们在小鼠中的初步数据表明：（i）O2-冷冻凝胶可以逆转局部 缺氧和恢复关键免疫细胞（树突状细胞; DC）的功能;（ii）一旦进入体内，冷冻凝胶疫苗 有效地定位移植的肿瘤细胞，可控地释放免疫调节因子， （iii）引发特异性和稳健的疫苗诱导的T细胞介导的抗肿瘤免疫应答。 免疫力在这里，我们将优化O2-冷冻凝胶的特性，以获得最大的抗肿瘤疗效和安全性; 并评估其抑制局部缺氧应激和改善DC募集、激活和归巢的能力 引流淋巴结最后，我们将在预防和治疗小鼠中测试O2-冷冻凝胶疫苗 前列腺癌模型，以确定它们诱导特异性、有效和持久的抗肿瘤活性的能力。 免疫反应。这一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治疗途径。 免疫疗法独立运作，但与其他疗法协同作用。

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.