REPROGRAMMING THE METASTATIC MICROENVIRONMENT OF PANCREATIC CANCER THROUGH CSF1R

描述(申请人提供)：胰腺癌(PC)患者的预后很差，5年生存率不到6%。这在一定程度上是由于PC倾向于 疾病检测之前的转移以及这些转移肿瘤对细胞毒治疗的抵抗力。胰腺癌的治疗抵抗很大一部分来自于独特的肿瘤微环境的支持。这种肿瘤微环境包括大量的浸润性髓系细胞，包括肿瘤相关的巨噬细胞，这些细胞通过诱导免疫抑制和增加肿瘤干细胞的存在来加剧对治疗的反应。因此，在临床可行的情况下，重新编程免疫微环境将改善对细胞毒治疗的反应，即使在耐药肿瘤中也是如此。解决这个问题的一个独特的方法是靶向克隆刺激因子1受体(CSF1R)。先前的研究表明，巨噬细胞募集、存活和激活的关键细胞因子集落刺激因子-1的遗传缺失可以减缓乳腺和神经内分泌肿瘤的进展。我们自己的工作表明，抑制CSF1R可以极大地改善对化疗的反应，并减少胰腺癌模型中的转移扩散。我们现在已经扩展了这些观察，并证明了CSF1R抑制1)快速重新编程肿瘤浸润性巨噬细胞反应，2)降低肿瘤起始细胞的频率，以及3)恢复中性粒细胞和T淋巴细胞的抗肿瘤细胞毒反应。在这样做的过程中，CSF1R抑制重新编程肿瘤微环境，以增加对化疗的反应，减少转移扩散。因此，我们的假设是，阻断CSF1R信号对肿瘤微环境进行重新编程，以改善对化疗和免疫治疗的反应。拟议研究的长期目标是启动新的临床试验，测试这种方法在转移性PC中的应用。然而，为了给这些试验提供信息并检验我们的总体假设，以下具体目标至关重要。目的1：确定巨噬细胞调控转移复发的机制。目的2：确定CSF1R拮抗剂在粒细胞重编程中的作用。目的3：确定针对CSF1R的最佳治疗方案，以提高免疫治疗水平。这些目标构成了我们拟议的研究的基础，该研究将使用临床可翻译药物和遗传小鼠模型的组合来：1)从根本上了解髓系细胞调节化疗反应的生物学基础。以及2)确定和验证目标，以利用这些生物过程获得治疗益处。因此，这项应用将开发靶向抑制CSF1R作为一种新的免疫治疗药物，以改善胰腺癌患者的预后。

DESCRIPTION (provided by applicant): The prognosis for pancreatic cancer (PC) patients is dismal, with a 5-year survival rate of less than 6%. This is in part due to the propensity of PC to metastasize prior to disease detection and the resistance of these metastatic tumors to cytotoxic therapies. A significant portion of therapeutic resistance in pancreatic cancers comes from the support of a unique tumor microenvironment. This tumor microenvironment includes significant numbers of infiltrating myeloid cells including tumor-associated macrophages, which exacerbate responses to therapy by inducing immunosuppression and increasing the presence of cancer stem cells. Thus, where clinically feasible reprogramming the immune microenvironment would improve responses to cytotoxic therapy even in resistant tumors. One unique approach to this problem is to target the colony-stimulating factor 1 receptor (CSF1R). Previous studies have shown that genetic loss of colony stimulating factor-1, a critical cytokine for the recruitment, survival, and activation of macrophages, can decease the progression of mammary and neuroendocrine pancreatic tumors. Our own work has shown that inhibiting CSF1R can vastly improve responses to chemotherapy and decrease metastatic spread in pancreatic tumor models. We have now extended these observations and demonstrated that CSF1R inhibition 1) rapidly reprograms tumor-infiltrating macrophage responses, 2) decreases the frequency of tumor initiating cells, and 3) leads to recovery of anti-tumor cytotoxic responses by neutrophils and T lymphocytes. In so doing, CSF1R inhibition reprograms the tumor microenvironment to increase responses to chemotherapy and decrease metastatic spread. Thus, our hypothesis is that blockade of CSF1R signaling reprograms the tumor microenvironment to improve responses to chemo- and immunotherapy. The long-term goals of the proposed studies are to initiate new clinical trials testing this approach in metastatic PC. However, in order to inform these trials and test our overall hypothesis the following specific aims are critical. Aim 1: Determine the mechanisms by which macrophages regulate metastatic relapse. Aim 2: Determine the functional role of CSF1R blockade in granulocyte reprogramming. Aim 3: Determine the optimum therapeutic regimen for targeting CSF1R to improve immunotherapy. These Aims form the basis of our proposed studies, which will use a combination of clinically translatable agents and genetic mouse models to: 1) fundamentally understand the biological underpinnings by which myeloid cells regulate chemotherapeutic response. And 2) to identify and validate targets to exploit these biological processes for therapeutic benefit. Thus, this application will develop targeted inhibition of CSF1R as a novel immunotherapeutic agent to improve outcomes for pancreatic cancer patients.