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

• 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
• 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

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）是一种侵略性疾病，幸存者很少。胰腺的进展 肿瘤形成需要与致癌突变合作时进行免疫抑制炎症。但是， PDA中促进肿瘤炎症的驱动因素知之甚少。 Dectin-1是C型凝集素的成员 模式识别受体的家族是对真菌病原体的先天免疫反应所必需的。然而， Dectin-1在无菌注射或促进肿瘤发生中没有确定的作用。非疾病原 衍生的Dectin-1配体尚未得到很好的特征。我们的初步数据表明，dectin-1高度 在小鼠和人类的PDA的炎症和上皮室中表达。此外，Dectin-1 结扎加速PDA的发育，而Dectin-1缺失受到保护。此外，我们发现 Galectin-9是一种对β-半乳糖苷的亲和力的讲座，在PDA肿瘤微环境中无处不在 连接Dectin-1。从机械上讲，我们发现肿瘤相关巨噬细胞（TAM）中的Dectin-1信号传导 诱导其重编程为导致TH2和Treg的免疫抑制M2样巨噬细胞 CD4+ T细胞在体内的分化。基于这些数据，我们假设Galectin-9的Dectin-1连接为 一个关键开关，可在胰腺TME中驱动免疫抑制。在AIM 1中，我们将确定 Dectin-1激活在PDA中的后果并测试靶向Dectin-1或Galectin-9是否受到保护，并且 扩展PDA潜水鼠模型中的生存​​。我们还将确定特定室（上皮与 炎症）其中dectin-1信号传导致癌。在AIM 2中，我们将测试我们的压倒性假设是 髓样细胞中的Dectin-1信号传导影响免疫抑制巨噬细胞亚群的差异膨胀 具有产生促肿瘤的T细胞的倾向，导致肿瘤的厌食症。我们也会 描述dectin-1依赖性适应性免疫的生化机制在PDA中并测试我们 转化假设，靶向Dectin-1将具有指向检查点受体的协同效率 免疫疗法方案。总体而言，AIM 2将定义Dectin-的细胞和生化机制 1促进PDA并为发展实验疗法的新策略提供指导。 AIM 3将致力于阐明Dectin-1信号在人PDA和 研究Dectin-1 – Galectin-9轴对抑制适应性免疫学和临床的影响 病理疾病的特征和患者的预后。我们预计通过Galectin-9激活Dectin-1是一个 PDA中免疫抑制性髓样细胞编程的主要驱动力，导致CD4+和CD8+ T细胞厌食。 我们认为我们的工作具有很高的翻译价值，并会表明Dectin-1和Galectin-9可能很有吸引力 患者实验疗法的靶标。此外，这项工作可能对角色具有深远的影响 用于其他癌症亚型和无菌炎症中的Dectin-1。