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

 描述(申请人提供)：胰腺癌(PAC)患者的预后很差。免疫疗法的应用有望彻底改变PAC患者的预后。不幸的是，到目前为止，在PAC中进行免疫治疗的尝试并没有像单一药物那样取得显著的临床益处。这可能是由于存在一种独特的抑制性肿瘤微环境(TME)，这种微环境在大多数胰腺导管腺癌(PDAC)中占主导地位。这种肿瘤保护微环境的两个主要驱动因素包括致密的纤维性肿瘤间质和支持肿瘤的髓系细胞的强大渗透。高间质密度为T细胞的渗透和功能提供了障碍。这些数据表明，如果我们能够找到重新编程保护性TME以促进免疫治疗的治疗方法，我们可以改善PAC患者的预后。其中一种方法是针对导致纤维化和抑制性PDAC TME的致癌途径。最近，我们发现粘着斑激酶(FAK)-1是PDAC肿瘤纤维化和炎性(纤维-炎症)TME的主要驱动因素。我们发现，在人类PDAC中，FAK活性升高与更高的纤维化水平、过多的髓细胞浸润和较差的T细胞反应相关。这些数据表明，FAK是阻碍免疫治疗效果的纤维炎症微环境的关键介质。我们发现，在PAC小鼠模型中，FAK抑制显著减少了纤维化和炎性髓系细胞的浸润，并改善了T细胞功能。我们的假设是：Kras突变的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信号在纤维化和肿瘤进展中的作用。3)确定FAK阻断改善免疫治疗的机制。意义：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是如何相互干扰而产生对免疫治疗的抵抗力的。这是我们对PAC免疫生物学的理解上的一个重大差距，到目前为止，PAC的免疫生物学已经阻碍了治疗的有效性。

 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.