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

基本信息

批准号：
10278330
负责人：
Prasenjit Dey
金额：
$ 42.79万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
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/10278330
关键词：
Allergic Disease Alternaria Antibodies Antifungal Agents Asthma Biological Biology CD4 Positive T Lymphocytes Cell Line Cells Clinical Clinical Research Combined Modality Therapy Cytokine Signaling Development Disease Epithelial Foundations Fungal Spores Future Genetically Engineered Mouse Human IL4 gene IL5 gene Immune Immune checkpoint inhibitor Immune response Immunomodulators Immunotherapy Infiltration Inflammatory Interleukin-13 KRASG12D Knock-out Knowledge Lung Lung diseases Lymphoid Cell 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 Pharmacology Play Pre-Clinical Model 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-infiltrating immune cells Work asthmatic patient base cancer cell cell injury clinical development clinically relevant cytokine effective therapy experimental study extracellular fungal microbiota fungus immune checkpoint immunotherapy trials improved insight macrophage mouse model mycobiome neoplastic cell neutralizing antibody novel novel strategies novel therapeutic intervention novel therapeutics overexpression pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pre-clinical receptor recruit therapy resistant tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

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，在很大程度上仍然存在无法治愈的。尽管对这种严重治疗耐药性的原因知之甚少，但部分原因是归咎于肿瘤微环境（TME）中存在的信号因子，它支持增殖和肿瘤细胞的存活。除了富含基质外，PDAC TME 还与一种独特的肿瘤相关免疫浸润。矛盾的是，大多数免疫治疗试验都使用免疫检查点抑制剂，或者作为单一疗法或联合疗法未能提高患者的生存率，促使人们探索新的治疗方法策略。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很大程度上仍未被探索。在最近的一项研究中，我们证明 TH2 分泌的细胞因子 IL4 和 IL13 细胞（CD4+ T 细胞的一种亚型）为 PDAC 发育提供营养支持。从机械上讲，抑制这种情况细胞因子介导的癌症-TH2细胞之间的串扰无论是在遗传上还是在药理学上都大大减少肿瘤生长并提高临床前模型中的存活率。我们随后的初步工作确定了一个有效的炎症细胞因子 IL33，由 PDAC 细胞过度表达和释放，吸引并激活 TH2 以及其他免疫细胞，例如先天淋巴细胞 2 (ILC2) 和 Tregs。重要的是，我们发现发布 PDAC 细胞对 IL33 的作用是由肿瘤内真菌组介导的。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，并伴随通过显着的 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 肿瘤发生中发挥重要作用，肿瘤内真菌组是 IL33 分泌的关键。该提案的主要目的是阐明真菌生物组在 IL33 介导的 2 型免疫中的作用反应并提供临床前证据以指导未来抗 IL33 单克隆抗体的临床研究在 PDAC 患者中。为此，我们将确定真菌生物组介导的 IL33 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 IL33， PDAC 患者肿瘤和血清样本中的肿瘤内真菌组和 2 型免疫细胞。虽然我们的使用同基因原位模型的初步研究表明，IL33 可使肿瘤显着消退缺失或抗真菌治疗，协同组合策略预计疗效更佳。因此，我们建议将抗 IL33 抗体与抗真菌治疗结合使用，以获得更好的疗效。最后，为了阻断 IL33-TH2/ILC2 轴，我们拥有三种基因工程小鼠模型，这将允许严格测试 IL33 在 PDAC 肿瘤发生中的功能。总之，我们的研究旨在确定一个针对 PDAC 患者的新策略，并为抗-PDAC 的未来临床开发提供机制见解 IL33治疗。