Role of type 2 immune response in pancreatic cancer tumorigenesis

胰腺导管腺癌（PDAC）是一种侵袭性疾病， 无法治愈虽然这种深刻的治疗阻力的原因知之甚少，但部分原因是 这归咎于肿瘤微环境（TME）中存在的信号因子，该因子支持肿瘤细胞的增殖和 肿瘤细胞的存活。除了富含间质外，PDAC TME还与独特的肿瘤相关 免疫浸润奇怪的是，大多数使用免疫检查点抑制剂的免疫治疗试验，无论是作为 单药治疗或联合治疗，未能增加患者生存率，促使探索新的治疗方法 战略布局为此，细胞因子介导癌细胞和免疫细胞之间的异型相互作用 大部分尚未开发。在最近的一项研究中，我们证明了TH 2分泌的细胞因子IL 4和IL 13， 细胞（CD 4 + T细胞的一种亚型）为PDAC发育提供营养支持。从机制上说，抑制这种 细胞因子介导的癌症-TH 2细胞之间的串扰在遗传上或免疫学上显著降低 肿瘤生长并增加临床前模型中的存活率。我们随后的初步工作确定了一种有效的 炎性细胞因子IL 33，其由PDAC细胞过度表达和释放，吸引并激活TH 2 和其它免疫细胞如先天淋巴样细胞2（ILC 2）和T淋巴细胞。重要的是，我们发现， PDAC细胞对IL 33的诱导作用是由肿瘤内真菌群介导的。IL 33的抑制或抗真菌治疗导致 2型免疫细胞（TH 2和ILC 2）和Treg细胞的浸润和活化减少， 显著的PDAC肿瘤消退综合这些观察结果，我们假设2型免疫 应答在PDAC肿瘤发生中起重要作用，并且肿瘤内真菌生物群系是IL 33分泌的关键。 该提议的主要目的是阐明真菌生物群系在IL 33介导的2型免疫应答中的作用。 反应，并提供临床前证据，以指导未来使用抗IL 33单克隆抗体进行的临床研究 在PDAC患者中。为此，我们将确定真菌群介导的IL 33释放的分子机制 在PDAC的细胞和类器官模型中。此外，为了进行临床相关研究，我们将分析IL 33， PDAC患者肿瘤和血清样品中的肿瘤内真菌生物群系和2型免疫细胞。虽然我们的 使用同系原位模型的初步研究已经显示了IL 33后显著的肿瘤消退 对于缺失或抗真菌治疗，预期协同组合策略在功效上甚至上级。 因此，我们提出使用抗IL 33抗体与抗真菌治疗组合以获得上级功效。 最后，为了阻断IL 33-TH 2/ILC 2轴，我们有三种基因工程小鼠模型， IL 33在PDAC肿瘤发生中的功能的严格测试。总之，我们的研究准备确定一个 针对PDAC患者的新策略，并为未来抗PDAC药物的临床开发提供机制见解。 IL 33治疗。

Project Summary: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that remains largely incurable. Although the cause for this profound therapeutic resistance is poorly understood, it is however partly blamed on signaling factors present in the tumor microenvironment (TME), which supports the proliferation and survival of neoplastic cells. Apart from being stroma rich, PDAC TME is associated with a distinctive tumor immune infiltrate. Paradoxically, most immunotherapy trials using immune checkpoint inhibitors, either as monotherapy or combination, failed to increase patient survival motivating exploration of new therapeutic strategies. To that end, the cytokine mediated heterotypic interactions between cancer cells and immune cells remain largely unexplored. In a recent study, we demonstrated that cytokines, IL4 and IL13, secreted by TH2 cells (a subtype of CD4+ T cells), provide trophic support for PDAC development. Mechanistically, inhibiting this cytokine mediated crosstalk between cancer-TH2 cells either genetically or pharmacologically drastically reduces tumor growth and increases survival in a preclinical model. Our subsequent preliminary work identified a potent inflammatory cytokine, IL33 which is overexpressed and released by PDAC cells that attract and activate TH2 and other immune cells such as innate lymphoid cells 2 (ILC2) and Tregs. Importantly, we found that the release of IL33 by PDAC cells is mediated by intratumor mycobiome. Inhibition of IL33 or anti-fungal treatment leads to a decrease in the infiltration and activation of type 2 immune cells (TH2 and ILC2) and Treg cells, accompanied by significant PDAC tumor regression. Taking these observations together, we hypothesize that type 2 immune response plays an important role in PDAC tumorigenesis and intratumor mycobiome is key to the IL33 secretion. The major objective of this proposal is to elucidate the role of mycobiome in the IL33 mediated type 2 immune response and provide pre-clinical evidence to guide future clinical studies with an anti-IL33 monoclonal antibody in PDAC patients. To that end, we will determine the molecular mechanism of mycobiome mediated IL33 release in cell and organoid models of PDAC. Further, to conduct a clinically relevant study, we will analyze IL33, intratumor mycobiome and type 2 immunocytes in the PDAC patient tumor and serum samples. While our preliminary studies using the syngeneic orthotopic model have shown a significant tumor regression upon IL33 deletion or anti-fungal treatment, synergistic combination strategies are expected to be even superior in efficacy. So, we propose to use an anti-IL33 antibody in combination with anti-fungal treatment for superior efficacy. Finally, to block the IL33-TH2/ILC2 axis we have three genetically engineered mouse models that will allow rigorous testing of the function of IL33 in PDAC tumorigenesis. In conclusion, our study is poised to identify a novel strategy to target PDAC patients and provide mechanistic insights for future clinical development of anti- IL33 therapy.