Role of type 2 immune response in pancreatic cancer tumorigenesis

2 型免疫反应在胰腺癌肿瘤发生中的作用

• 批准号: 10662252
• 负责人: Prasenjit Dey
• 金额: $ 39.91万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662252
• 关键词: Allergic Disease; Alternaria; Antibodies; Antifungal Agents; Biological; Biology; CD4 Positive T Lymphocytes; Cell Line; Cells; Clinical; Clinical Research; Combined Modality Therapy; Cytokine Signaling; Development; Disease; Epithelium; Foundations; Fungal Spores; Future; Genetically Engineered Mouse; Human; IL4 gene; IL5 gene; Immune; Immune checkpoint inhibitor; Immune response; Immunoprecipitation; Immunotherapy; Infiltration; Inflammatory; Interleukin-13; KRASG12D; Knock-out; Knowledge; Lung; Lung diseases; Lymphoid Cell; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Modeling; Molecular; Monoclonal Antibodies; Mus; Mycoses; Normal Cell; Oncogenes; Oral; Organoids; P2Y2 receptor; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Play; Pre-Clinical Model; Proliferating; Proteomics; Regulatory T-Lymphocyte; Reporting; Research; Ribosomal RNA; Role; Sampling; Serum; Signal Transduction; Sphincter of Oddi structure; Subcellular Fractions; Survival Rate; Testing; Th2 Cells; Therapeutic; Transplantation; Tumor Promotion; Tumor-infiltrating immune cells; Work; asthma exacerbation; asthmatic patient; cancer cell; cell injury; clinical development; clinically relevant; cytokine; effective therapy; experimental study; extracellular; fungal microbiota; fungus; immune checkpoint; immune modulating agents; immunotherapy trials; improved; insight; mouse model; mycobiome; neoplastic cell; neutralizing antibody; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pharmacologic; pre-clinical; receptor; recruit; therapy resistant; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; validation studies

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.

项目摘要：胰腺导管腺癌(PDAC)是一种侵袭性疾病，大部分残留 不治之症。尽管这种深刻的治疗耐药性的原因尚不清楚，但它在一定程度上是 归咎于肿瘤微环境(TME)中存在的信号因子，它支持肿瘤的增殖和 肿瘤细胞的存活。除了间质丰富外，PDAC TME还与一种独特的肿瘤有关 免疫渗透。矛盾的是，大多数使用免疫检查点抑制剂的免疫治疗试验，要么是 单一治疗或联合治疗未能提高患者存活率激励探索新的治疗方法 战略。为此，细胞因子介导了癌细胞和免疫细胞之间的异型相互作用 很大程度上仍未被勘探。在最近的一项研究中，我们证明了TH2分泌的细胞因子IL4和IL13 细胞(CD4+T细胞的一个亚型)，为PDAC的发育提供营养支持。从机制上讲，抑制这种 细胞因子介导的肿瘤-TH2细胞之间的串扰在基因或药物上显著降低 在临床前模型中，肿瘤生长和提高存活率。我们随后的初步工作发现了一种有效的 炎性细胞因子IL33，由PDAC细胞过度表达和释放，可吸引和激活TH2 以及其他免疫细胞，如先天淋巴样细胞2(ILC2)和树突状细胞。重要的是，我们发现这个版本 PDAC细胞对IL33的杀伤作用是由瘤内真菌生物体介导的。抑制IL33或抗真菌治疗会导致 2型免疫细胞(TH2和ILC2)和Treg细胞的浸润和激活减少，伴随 通过显著的PDAC肿瘤消退。综合这些观察结果，我们假设2型免疫 反应在PDAC肿瘤的发生中起重要作用，而瘤内真菌生物群是分泌IL33的关键。 这项建议的主要目的是阐明真菌生物体在IL33介导的2型免疫中的作用。 并提供临床前证据，以指导未来使用抗IL33单抗进行临床研究 在PDAC患者中。为此，我们将确定霉菌群介导的IL33释放的分子机制 在PDAC的细胞和器官模型中。此外，为了进行临床相关研究，我们将分析IL33， PDAC患者肿瘤和血清标本中的瘤内真菌菌群和2型免疫细胞。而我们的 使用同种异体原位模型的初步研究表明，IL33的肿瘤有显著的消退 无论是缺失还是抗真菌治疗，协同联合策略有望在疗效上更胜一筹。 因此，我们建议联合使用抗IL33抗体和抗真菌治疗，以获得更好的疗效。 最后，为了阻断IL33-TH2/ILC2轴，我们有三个基因工程小鼠模型，将允许 严格检测IL33在PDAC肿瘤发生中的作用。总而言之，我们的研究准备确定一个 以PDAC患者为目标的新策略，并为未来抗心绞痛的临床发展提供机械性见解 IL33疗法。