Targeting Focal Adhesion Kinase to Improve RT-inducted Tumor Immunity

项目总结 PDAC对多种药物的耐药性部分与其独特的肿瘤微环境有关 (TME)，其特征是由致密的富胶原细胞外基质组成的结缔组织间质 (ECM)、丰富和多样化的肿瘤相关成纤维细胞(CAF)以及由此产生的肿瘤细胞 缺氧。PDAC的纤维化间质导致药物传递不良，缺乏渗透和抗肿瘤功能。 肿瘤免疫细胞。这三个方面与PDAC对化疗和化疗的耐药性有关 免疫疗法。然而，目前尚不清楚PDAC相关的促结缔组织增生和纤维化可能会产生怎样的影响。 对RT的抗性。历史研究主要集中在放射疗法(RT)作为损伤的直接机制。 肿瘤细胞增殖导致双链DNA断裂积累和细胞死亡。它也是 认识到RT可以通过释放肿瘤衍生的抗原和危险信号来启动抗肿瘤免疫， 这可能在多种癌症类型的RT疗效中起着关键作用。然而，目前还不清楚这些是否 在像PDAC这样的高度纤维化和免疫抑制的癌症中，RT的免疫启动功能是完整的。 我们实验室以前的工作表明，抑制粘着斑激酶(FAK)是一种 在PDAC中激活，减少肿瘤相关纤维化，从而改善对化疗和检查点的反应 免疫疗法14，15。这些研究已经进入临床试验，早期结果令人振奋。然而，我们的 最近的数据表明，FAK可以与RT加T细胞检查点组合更有效地协同作用。 基于这些数据，我们假设纤维化间质参与了PDAC对RT和RT-1的抵抗。 诱导肿瘤免疫。为了测试这一点，我们将： 目的1.确定纤维化损害RT效应的机制(S)以及FAK抑制是如何克服的 这。 目的2：确定抑制FAK是否能增强RT诱导的局部抗肿瘤免疫和疾病控制 晚期PDAC患者。 目的3：确定抑制粘着斑信号通路改善RT诱导的检查点的机制(S 免疫治疗反应。 影响：研究纤维化如何对PDAC的RT疗效产生负面影响将进一步加深我们对如何 将基质靶向药物整合到当前的RT方案中，最终目标是提高RT的疗效。

PROJECT SUMMARY The resistance of PDAC to multiple agents, has been linked in part to its unique tumor microenvironment (TME), which is characterized by a desmoplastic stroma composed of dense collagen-rich extracellular matrix (ECM), abundant and diverse populations of cancer associated fibroblasts (CAFs), and resultant tumor cell hypoxia. PDAC’s fibrotic stroma contributes to poor drug delivery, and deprived infiltration and function of anti- tumor immune cells. These three aspects have been linked to PDAC resistance to both chemo- and immunotherapy. However, it is not clear how the PDAC-associated desmoplasia and fibrosis might impact resistance to RT. Historical studies have focused on radation therapy (RT) as a direct mechanism to damage proliferating tumor cells leading to the accumulation of double-strand DNA breaks and cell death. It is also appreciated that RT can prime anti-tumor immunity by releasing tumor-derived antigens and danger signals, and that this likely plays a critical role in RT efficacy in multiple cancer types. However, it is unclear if these immune priming functions of RT are intact in a highly fibrotic and immunosupressive cancers like PDAC. Previous work from our lab demonstrated that inhibition of Focal Adhesion Kinase (FAK), which is hyper activated in PDAC, reduced tumor-associated fibrosis and thus improves responses to chemo- and checkpoint immunotherapies14,15. These studies have moved to clinical trials with promising early results. However, our recent data suggest FAK can synergize even more effectively with RT plus T cell checkpoint combinations. Based on these data, we hypothesize that fibrotic stroma contributes to PDAC resistance to RT and RT- induction of tumor immunity. To test this we will: Aim 1. Determine the mechanism(s) by which fibrosis impairs RT efficacy and how FAK inhibition overcomes this. Aim 2: Determine if FAK inhibition enhances RT-induced anti-tumor immunity and disease control in locally advanced PDAC patients. Aim 3: Determine the mechanism(s) by which inhibition of FAK signaling improves RT-induced checkpoint immunotherapy response. Impact: Studying how fibrosis negatively impacts RT efficacy in PDAC will further our understanding of how to integrate a stromal targeted agents into current RT regimens with the ultimate goal of improving efficacy of RT.