(PQ11) Targeting STING in the context of chemoradiation therapy to overcome poor preexisting immunity in mouse models of pancreatic cancer.

项目摘要 近三分之二的癌症患者将在治疗期间接受放射治疗(RT)，但放射治疗的 治疗潜力仅限于在最终或辅助环境中的局部区域疾病。当地 晚期不能切除的疾病占确诊的胰腺癌患者的30%-40%，并携带5%- 一年存活率不到1%。虽然RT在转移性癌症中经常使用并高度有效，但对于 缓解症状性疾病，对未受照射的远端部位影响不大，因此对 在转移的环境中生存。同样，在局部晚期地区性疾病的背景下，如在 胰腺癌，放射治疗在新辅助治疗环境中经常被研究，但鲜有明显的证据。 总体存活率的提高。我们已经发现，放射治疗激活了脑内的髓系反应。 抑制适应性免疫的肿瘤。通过靶向SING(干扰素基因刺激物)传感器 对于环二核苷酸(CDN)，我们发现我们可以防止抑制性髓系反应，并且当 CDN与放射治疗相结合，可以控制侵袭性小鼠肿瘤。我们假设 提供刺激性配体与放化疗相结合可消除贫血组的生物标记物 对免疫治疗的反应。我们认为，在被招募到的系统性单核细胞中结扎STING 放射和/或化疗后的肿瘤阻止了向促肿瘤环境的过渡和 增强肿瘤相关T细胞反应。本研究的具体目的是：1.检验假设 胰腺癌的多组分放化疗包含关键的核心成分 当结合全身刺激性配体治疗时，产生适应性肿瘤特异性免疫反应；2： 验证以下假设：全身刺激性配体联合 放射治疗和/或化疗是由于复极化的单核细胞重新聚集到肿瘤中而导致的 在治疗后的肿瘤环境中反过来促进获得性免疫；3：检验假设 通过刺激性配体靶向髓室的免疫疗法将被要求用于患有 原有免疫力差和高度髓系受累的生物标记物。我们的研究设计包含了 免疫状态下可移植和自发胰腺癌模型的临床前放化疗 使用先进的成像和治疗平台的合格小鼠。这项建议特别侧重于 控制局部和远处疾病，扩大肿瘤免疫治疗的潜力 病人。

Project Summary Nearly two-thirds of all cancer patients will receive radiation therapy (RT) during treatment, but radiation's curative potential is limited to local-regional disease in either the definitive or adjuvant setting. Locally advanced, unresectable disease represents 30-40% of pancreatic cancer patients at diagnosis and carries a 5- year survival rate of less than 1%. While RT is frequently used and highly effective in metastatic cancer for palliation of symptomatic disease, it has little impact on unirradiated distant sites and thus no impact on survival in the metastatic setting. Likewise in the setting of locally advanced regional disease, such as in pancreatic cancer, radiation is frequently studied in the neoadjuvant setting but with little apparent improvement in overall survival. We have found that radiation therapy activates a myeloid response in the tumor that suppresses adaptive immunity. By targeting the STING (STimulator of INterferon Genes) sensor with cyclic dinucleotides (CDN), we have found that we can prevent suppressive myeloid responses, and when CDN are combined with radiation therapy we can control aggressive murine tumors. We hypothesize that provision of STING ligands in combination with chemoradiation therapy removes the biomarkers of poor response to immunotherapy. We propose that ligation of STING in systemic monocytes that are recruited to tumors following radiation and/or chemotherapy prevents transition to a tumor-promoting environment and enhances tumor associated T cell responses. The specific aims of this study are to 1: Test the hypothesis that the multicomponent chemoradiation therapy for pancreatic cancer contains core components critical to generate adaptive tumor-specific immune response when combined with systemic STING ligand treatment; 2: Test the hypothesis that the enhanced tumor control provided by systemic STING ligand in combination with radiation therapy and/or chemotherapy results from recruitment of repolarized monocytes to the tumor that in turn promote adaptive immunity in the post-treatment tumor environment; 3: Test the hypothesis that immunotherapies targeting the myeloid compartment via STING ligands will be required for tumors with the biomarkers of poor preexisting immunity and high myeloid involvement. Our study design incorporates preclinical chemoradiation therapy of transplantable and spontaneous models of pancreatic cancer in immune competent mice using an advanced imaging and treatment platform. This proposal particularly focuses on control of both local-regional and distant disease to extend the curative potential of immunotherapy for cancer patients.