Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers

针对PD-1的检查点阻断抗体显示出转移性头部和 颈部鳞状细胞癌(HNSCC)患者通过重新激活已渗透到 肿瘤微环境。然而，PD-1封锁的总体应答率仍然较低，约为18%， 提示不同的治疗结果是由于患者疾病的内在差异，如 作为肿瘤微环境。最近，我们开发了一种新的放射增强剂，纳米级金属- 有机骨架(NMOF)，可以改变免疫微环境。通过协调构建 在Hf-oxo簇合物和类似卟啉的分子之间，nMOF产生羟基自由基和 单线态氧在称为放射治疗-放射动力学治疗(RT-RDT)的过程中。这件事的目的是 应用是定义RT-RDT和nMOF使能的免疫疗法改变 免疫微环境，以使HNSCCs对检查站封锁敏感。我们的中心假设是 NMOF可递送CpG寡核苷酸并与RT-RDT诱导的抗原释放协同作用 和I型干扰素表达，刺激CD8+和CD4+T细胞增殖和渗入HNSCCs PD-1/PD-L1受体阻滞剂对照射和非照射肿瘤均有逆转作用。这件事的目标是 建议的研究是确定一种新的治疗方法，并确定其改变免疫的机制。 微环境使HNSCCs和可能的其他癌症对当前的临床免疫疗法敏感。这 项目将使用创新的分子可调nMOF，通过独特的 RT-RDT机制。这项建议意义重大，因为它解决了治疗辐射抵抗的未得到满足的需求。 和转移性HNSCCs直接通过RT-RDT和作为免疫刺激剂来增强 现有检查点抑制剂的有效性。这项提议将通过追求四个具体的 目的：(1)明确RT-RDT后天然免疫激活的细胞机制；(2)确定RT-RDT如何激活天然免疫 RDT对鳞癌肿瘤微环境的影响；(3)评价不同RDT对肿瘤微环境的影响 免疫成分对RT-RDT和免疫联合治疗疗效的影响；(4)确定疗效 耐PD-1/PD-L1阻滞剂的HNSCCs的治疗AIM 1将治疗细胞和体外刺激的或 用nMOF和辐射培养免疫成分以确定RT-RDT如何启动刺痛和I型 肿瘤微环境中的干扰素信号。目标2将确定肿瘤微环境和 细胞外基质受nMOF介导的RT-RDT的影响。目标3将评估不同的 免疫成分对nMOF抗癌效果的影响。AIM 4将使用原始口腔肿瘤模型，该模型 抵抗PD-1/PD-L1阻断作为识别协同作用的新型免疫治疗组合的模型 RT-RDT。最终，该项目将提供新的治疗策略，使用临床相关 纳米药物，以增强HNSCCs的放射治疗和免疫排斥反应。

Checkpoint blockade antibodies targeting PD-1 have demonstrated improved survival in metastatic head and neck squamous cell carcinomas (HNSCC) patients by reactivating effector T cells that have infiltrated the tumor microenvironment. However, PD-1 blockade still has low overall response rates approximating 18%, suggesting that the different treatment outcomes are due to intrinsic differences in the patients' diseases, such as tumor microenvironments. Recently, we have developed a new class of radioenhancers, nanoscale metal- organic frameworks (nMOFs), that can alter the immune microenvironment. Constructed via coordination between hafnium-oxo clusters and porphyrin-like molecules, nMOFs generate both hydroxyl radicals and singlet oxygen in a process termed radiotherapy-radiodynamic therapy (RT-RDT). The objective in this application is to define the mechanisms by which RT-RDT and nMOF-enabled immunotherapy alter the immune microenvironment in order to sensitize HNSCCs to checkpoint blockade. Our central hypothesis is that nMOFs can deliver the CpG oligodeoxynucleotides and synergize with RT-RDT-induced antigen release and Type I IFN expression, which stimulates CD8+ and CD4+ T cell proliferation and infiltration into HNSCCs to regress both irradiated and non-irradiated tumors treated with PD-1/PD-L1 blockade. The goal for this proposed research is to identify a novel therapy and define the mechanisms by which it alters the immune microenvironment to sensitize HNSCCs and possibly other cancers to current clinical immunotherapies. This project will use innovative molecularly tunable nMOFs having unprecedented radioenhancement via the unique RT-RDT mechanism. This proposal is significant because it addresses an unmet need of treating radioresistant and metastatic HNSCCs both directly via RT-RDT and by acting as an immunostimulant to enhance the efficacy of existing checkpoint inhibitors. This proposal will test the central hypothesis by pursuing four specific aims: (1) define the cellular mechanisms of innate immune activation after RT-RDT; (2) determine how RT- RDT affects the tumor microenvironment in squamous cell cancers; (3) evaluate the contributions of different immune components on the efficacy of RT-RDT and immunotherapy combinations; and (4) determine effective therapies for HNSCCs resistant to PD-1/PD-L1 blockade. Aim 1 will treat cells and ex vivo stimulated or cultured immune components with nMOFs and radiation to determine how RT-RDT initiates STING and Type I interferon signaling in the tumor microenvironment. Aim 2 will determine how the tumor microenvironment and extracellular matrix are affected by nMOF-mediated RT-RDT. Aim 3 will evaluate the contribution of different immune components to the anticancer efficacy of nMOFs. Aim 4 will use primary oral tumor models that are resistant to PD-1/PD-L1 blockade as a model to identify novel immunotherapy combinations that synergize with RT-RDT. Ultimately, this project will afford new therapeutic strategies using clinically relevant nanomedicines to enhance both the radiation therapy and immunological rejection of HNSCCs.