Interrupting Cellular Crosstalk in the Immunosuppressive Microenvironment of Pancreas Cancer

摘要 免疫疗法在许多恶性肿瘤的治疗中显示出巨大的前景，但 目前在治疗胰腺导管腺癌(PDA)方面尚未被证明是有效的 医疗模式。其中一个可能的原因是胰腺癌独特的生物学特性 建立免疫抑制微环境。我们发现这种交叉交流 肿瘤相关成纤维细胞(CAF)、肿瘤相关巨噬细胞(TAMs)和 肿瘤细胞是至关重要的。使用PDA的动物模型，我们发现肿瘤细胞极化 巨噬细胞通过激活CAF产生IL-6和通过产生特异性IL-6而产生TAM 代谢物。然后，TAMS和TAMs都通过产生精氨酸来抑制免疫反应 精氨酸酶1和通过产生EGFR配体，主要是HBEGF来刺激胰腺癌 细胞表达免疫检查点配体PDL1。我们建议结合使用 匹配的人源化患者来源异种移植(PDX)，由以下组成的有机培养系统 癌细胞、免疫细胞和CAF(即“微肿瘤”)和一种独特的双重重组酶 用基因工程的小鼠PDA模型来验证这样一种假设，即用 STAT3、HBEGF、ARG1或MEK的抑制剂将与PD1抑制有效地协同作用， 克服胰腺癌造成的强大免疫抑制 微环境。

Abstract Immune therapy has shown great promise in the treatment of a number of malignancies, but has not proven fruitful in fighting pancreatic ductal adenocarcinoma (PDA) using current modalities. One possible reason for this is the unique biology of the pancreatic cancer in establishing an immune suppressive microenvironment. We find that cross communication between cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs) and tumor cells is critical. Using animal models of PDA, we find that tumor cells polarize macrophages to TAMs both by activating CAFs to produce IL6 and by producing specific metabolites. TAMs then both suppress the immune response by arginine depletion by making Arginase 1 and by producing EGFR ligands, primarily HBEGF, to stimulate pancreatic cancer cells to express PDL1, an immune checkpoint ligand. We propose to use a combination of matched humanized patient derived xenografts (PDXs), organoid culture systems made up of cancer cells, immune cells and CAFs (ie “microtumors”) and a unique dual recombinase genetically engineered mouse model of PDA to test the hypothesis that treatment of tumors with inhibitors of STAT3, HBEGF, ARG1 or MEK will effectively synergize with PD1 inhibition, overcoming the powerful immune suppression created by the pancreatic cancer microenvironment.