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希望，但 尚未证明使用目前的抗胰腺导管腺癌（PDA）药物治疗有效。 方式。其中一个可能的原因是胰腺癌的独特生物学特性， 建立免疫抑制微环境。我们发现交叉交流 癌症相关成纤维细胞（CAF）、肿瘤相关巨噬细胞（TAM）和 肿瘤细胞是关键。使用PDA的动物模型，我们发现肿瘤细胞在肿瘤细胞中表达， 巨噬细胞通过激活CAF产生IL 6和通过产生特异性 代谢物。然后，TAMs通过使精氨酸耗尽来抑制免疫反应， 精氨酸酶1和通过产生EGFR配体，主要是HBEGF，刺激胰腺癌 细胞表达PDL1，一种免疫检查点配体。我们建议使用以下组合 匹配的人源化患者来源的异种移植物（PDX），由以下组成的类器官培养系统： 癌细胞、免疫细胞和CAF（即“微肿瘤”）和独特的双重重组酶 基因工程小鼠PDA模型，以检验用 STAT3、HBEGF、ARG1或MEK的抑制剂将有效地与PD1抑制协同作用， 克服了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.