COMBINED TUMOR AND STROMAL TARGETING TO IMPROVE PANCREATIC CANCER RESPONSE TO IMMUNOTHERAPY

 描述（由申请人提供）：胰腺癌（PaC）患者的预后令人沮丧。免疫疗法的应用有望彻底改变PaC患者的预后。不幸的是，迄今为止，在PaC中的免疫疗法的尝试作为单一药剂尚未实现显著的临床益处。这可能是由于在大多数胰腺导管腺癌（PDAC）中占主导地位的独特抑制性肿瘤微环境（TME）的存在。这种肿瘤保护性微环境的两个主要驱动因素包括致密的纤维化肿瘤基质和肿瘤支持性骨髓细胞的强烈浸润。高基质密度为T细胞浸润和功能提供了屏障。这些数据表明，如果我们能够确定重新编程保护性TME以促进免疫治疗的治疗方法，我们可以改善PaC患者的结局。一种这样的方法是靶向诱导纤维化和抑制性PDAC TME的致癌途径。 最近，我们已经确定了粘着斑激酶（FAK）-1，这是过度激活的突变的Kras的存在下，作为一个主要的驱动程序的纤维化和炎症（纤维炎症）TME的PDAC肿瘤。我们已经发现，在人PDAC中，FAK活性升高与较高的纤维化水平、过度的骨髓细胞浸润和较差的T细胞应答相关。这些数据表明，FAK是阻断免疫功效的纤维炎症微环境的关键介质。我们发现FAK抑制显著减少了PaC小鼠模型中的纤维化和炎性骨髓细胞浸润，并改善了T细胞功能。我们的假设是：Kras突变胰腺肿瘤和基质细胞之间的相互串扰调节炎性纤维化并阻止对免疫治疗的反应性。为了验证这一假设，我们将：1）确定Kras驱动的FAK活性调节纤维化和局部免疫抑制的机制。2)确定间质FAK信号传导对纤维化和肿瘤进展的影响。3)确定FAK阻断改善免疫治疗的机制。重要性：我们的初步数据强烈支持在PDAC患者中联合使用FAK抑制剂和化疗和/或检查点拮抗剂。然而，了解PDAC肿瘤和基质细胞中FAK信号传导驱动肿瘤纤维化和免疫抑制的机制对于设计有效的临床试验至关重要。此外，这些研究将有助于我们理解肿瘤细胞和基质细胞如何相互作用以产生对免疫疗法的抗性。这是我们对PaC免疫生物学理解的一个重大差距，这阻碍了迄今为止治疗的有效性。

 DESCRIPTION (provided by applicant): The prognosis for pancreatic cancer (PaC) patients is dismal. The application of immunotherapy holds the promise to revolutionize PaC patient outcomes. Unfortunately, attempts at immunotherapy in PaC, to date, have not achieved significant clinical benefits as single agents. This is likely due to the presence of a uniquely suppressive tumor microenvironment (TME) that is dominant in most pancreatic ductal adenocarcinomas (PDAC). Two major drivers of this tumor protective microenvironment include a dense fibrotic tumor stroma and robust infiltration by tumor-supportive myeloid cells. High stromal density provides a barrier to T cell infiltration and function. These data suggest that we could improve PaC patient outcomes, if we could identify therapeutics that reprogram the protective TME to facilitate immunotherapy. One such approach is to target the oncogenic pathways that induce the fibrotic and suppressive PDAC TME. Recently, we have identified focal adhesion kinase (FAK)-1, which is hyperactivated in the presence of mutated Kras, as a major driver of the fibrotic and inflammatory (fibro-inflammatory) TME of PDAC tumors. We have discovered that in human PDAC, elevated FAK activity correlates with higher fibrosis levels, excessive myeloid cell infiltration, and poor T cell responses. These data suggest that FAK is a key mediator of the fibro-inflammatory microenvironment that blocks immunotherapeutic efficacy. We have found that FAK inhibition dramatically reduced fibrosis and inflammatory myeloid cell infiltration, and improved T cell function in PaC mouse models. Our hypothesis is that: Reciprocal crosstalk between Kras-mutant pancreatic tumors and stromal cells regulates inflammatory fibrosis and prevents responsiveness to immunotherapy. To test this hypothesis, we will: 1) Determine the mechanisms by which Kras-driven FAK activity regulates fibrosis and local immunosuppression. 2) Determine the impact of stromal FAK signaling on fibrosis and tumor progression. 3) Determine the mechanisms by which FAK blockade improves immunotherapy. Significance: Our preliminary data strongly support the use of FAK inhibitors in combination with chemotherapy and/or checkpoint antagonists in PDAC patients. However, understanding the mechanisms by which FAK signaling in PDAC tumor and stromal cells drive tumor fibrosis and immunosuppression is critical to designing effective clinica trials. Additionally, these studies will contribute to our understanding of how tumor cells and stromal cells crosstalk to generate resistance to immunotherapy. This is a significant gap in our understanding of the immunobiology of PaC, which has thwarted the effectiveness of therapy to date.