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Dectin-1 signaling drives pancreatic oncogenesis by inducing macrophage-mediated adaptive immune suppression

Dectin-1 信号传导通过诱导巨噬细胞介导的适应性免疫抑制来驱动胰腺肿瘤发生

基本信息

批准号：
10054171
负责人：
DAFNA BAR-SAGI
金额：
$ 38.77万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054171
关键词：
Adaptor Signaling Protein Affinity Antifungal Agents Antigens Binding Biochemical C-Type Lectins CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Data Development Disease Disease Outcome Disease Progression Epithelial Epithelial Cells Family Galactose Binding Lectin Galactosides Growth Human Immune Immune Tolerance Immune response Immunosuppression Immunotherapeutic agent Immunotherapy Incidence Inflammation Inflammatory Innate Immune Response Interruption Investigation Investigational Therapies Lectin Ligands Ligation Malignant Neoplasms Mediating Mus Mutation Myeloid Cells Myeloid-derived suppressor cells Oncogenic Outcome Pancreatic Ductal Adenocarcinoma Pathologic Patients Pattern recognition receptor Phenotype Population Regimen Regulation Regulatory T-Lymphocyte Role Signal Transduction Sterility Survivors T cell anergy T cell differentiation T-Lymphocyte Testing Therapeutic Tumor-associated macrophages Work adaptive immunity adverse outcome anergy base beta-Glucans cancer subtypes checkpoint receptors cytotoxic CD8 T cells dectin 1 effector T cell immunogenic immunosuppressive macrophages in vivo macrophage member mortality mouse model novel novel strategies pancreatic ductal adenocarcinoma model pancreatic neoplasm pancreatic tumorigenesis pathogenic fungus promoter recruit synergism tumor tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

Summary Pancreatic ductal adenocarcinoma (PDA) is an aggressive disease with few survivors. Progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of tumor-promoting inflammation in PDA are poorly understood. Dectin-1 is a member of the C-type Lectin family of pattern recognition receptors and is required for the innate immune response to fungal pathogens. However, Dectin-1 does not have an established role in sterile inflammation or in promoting oncogenesis. Non-pathogen- derived Dectin-1 ligands have not been well-characterized. Our preliminary data showed that Dectin-1 in highly expressed in both the inflammatory and epithelial compartments in PDA in mice and humans. Moreover, Dectin-1 ligation accelerated PDA development whereas Dectin-1 deletion was protective. Further, we discovered that Galectin-9, a lectin with affinity for β-galactosides, is ubiquitous within the PDA tumor microenvironment and avidly ligates Dectin-1. Mechanistically, we found that Dectin-1 signaling in tumor-associated macrophages (TAMs) induces their reprogramming into immune-suppressive M2-like macrophages leading to Th2 and Treg differentiation of CD4+ T cells in vivo. Based on these data, we postulate that Dectin-1 ligation of Galectin-9 is a pivotal switch which drives immune-suppression in the pancreatic TME. In Aim 1 we will determine the consequences of Dectin-1 activation in PDA and test whether targeting Dectin-1 or Galectin-9 are protective and extend survival in diverse murine models of PDA. We will also determine the specific compartment (epithelial vs inflammatory) in which Dectin-1 signaling is oncogenic. In Aim 2 we will test our overriding hypothesis is that Dectin-1 signaling in myeloid cells induces the differential expansion of immune-suppressive macrophage subsets which have the proclivity to generate pro-tumorigenic T cells leading to tumor-permissive anergy. We also will delineate the biochemical mechanism of Dectin-1-dependant adaptive immune anergy in PDA and test our translational hypothesis that targeting Dectin-1 will have synergistic efficacy with checkpoint-receptor directed immunotherapeutic regimens. Collectively, Aim 2 will define the cellular and biochemical mechanisms of Dectin- 1 promotion of PDA and provide guidance for the development of novel strategies for experimental therapeutics. Aim 3 will be dedicated to elucidating the immune-suppressive effects of Dectin-1 signaling in human PDA and studying the implications of the Dectin-1–Galectin-9 axis on suppression of adaptive immunity and clinico- pathologic disease features and outcome in patients. We anticipate that Dectin-1 activation via Galectin-9 is a principal driver of immune-suppressive myeloid cell programming in PDA leading to CD4+ and CD8+ T-cell anergy. We believe our work has high translational value and will suggest that Dectin-1 and Galectin-9 may be attractive targets for experimental therapy in patients. Moreover, this work is likely to have far-reaching implications for a role for Dectin-1 in other cancer subtypes and in sterile inflammation.

概括胰腺导管腺癌（PDA）是一种侵袭性疾病，幸存者很少。胰腺的进展肿瘤发生需要免疫抑制炎症与致癌突变的配合。然而， PDA 中促肿瘤炎症的驱动因素尚不清楚。 Dectin-1是C型凝集素的成员模式识别受体家族，是针对真菌病原体的先天免疫反应所必需的。然而， Dectin-1 在无菌炎症或促进肿瘤发生中没有确定的作用。非病原体- 衍生的 Dectin-1 配体尚未得到充分表征。我们的初步数据表明 Dectin-1 高度在小鼠和人类 PDA 的炎症和上皮区室中表达。此外，Dectin-1 连接加速了 PDA 的发育，而 Dectin-1 缺失则具有保护作用。进一步，我们发现 Galectin-9 是一种对 β-半乳糖苷具有亲和力的凝集素，在 PDA 肿瘤微环境中普遍存在，并且被广泛应用。连接 Dectin-1。从机制上讲，我们发现肿瘤相关巨噬细胞 (TAM) 中的 Dectin-1 信号传导诱导其重编程为免疫抑制性 M2 样巨噬细胞，从而产生 Th2 和 Treg CD4+T细胞在体内的分化。根据这些数据，我们假设 Dectin-1 与 Galectin-9 的连接是驱动胰腺 TME 免疫抑制的关键开关。在目标 1 中，我们将确定 Dectin-1 在 PDA 中激活的后果，并测试靶向 Dectin-1 或 Galectin-9 是否具有保护作用和延长不同 PDA 小鼠模型的生存期。我们还将确定特定的隔室（上皮细胞与炎症），其中 Dectin-1 信号传导具有致癌性。在目标 2 中，我们将测试我们最重要的假设是骨髓细胞中的 Dectin-1 信号传导诱导免疫抑制巨噬细胞亚群的差异扩张具有产生促肿瘤 T 细胞的倾向，导致肿瘤无反应性。我们也会描述 PDA 中 Dectin-1 依赖性适应性免疫无能的生化机制并测试我们的翻译假设：靶向 Dectin-1 将与检查点受体定向具有协同功效免疫治疗方案。总的来说，目标 2 将定义 Dectin 的细胞和生化机制 1 推广PDA并为实验治疗新策略的开发提供指导。目标 3 将致力于阐明 Dectin-1 信号传导在人类 PDA 和研究 Dectin-1–Galectin-9 轴对抑制适应性免疫和临床的影响患者的病理疾病特征和结果。我们预计 Dectin-1 通过 Galectin-9 激活是一种 PDA 中免疫抑制性骨髓细胞编程导致 CD4+ 和 CD8+ T 细胞无反应的主要驱动因素。我们相信我们的工作具有很高的转化价值，并表明 Dectin-1 和 Galectin-9 可能很有吸引力患者实验治疗的目标。此外，这项工作可能会对一个角色产生深远的影响 Dectin-1 在其他癌症亚型和无菌炎症中的作用。