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: 10359672
• 负责人: DAFNA BAR-SAGI
• 金额: $ 38万
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359672
• 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.

总结 胰腺导管腺癌（PDA）是一种侵袭性疾病，很少有幸存者。胰腺癌进展 肿瘤发生需要免疫抑制性炎症与致癌突变协同作用。但 PDA中促肿瘤炎症的驱动因素知之甚少。Dectin-1是C型凝集素家族的一员 是模式识别受体家族的成员，是对真菌病原体的先天免疫应答所必需的。然而，在这方面， Dectin-1在无菌性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。我们的初步数据显示，Dectin-1在高水平 在小鼠和人的PDA的炎症和上皮区室中表达。此外，Dectin-1 连接促进PDA的发展，而Dectin-1缺失则具有保护作用。此外，我们发现， 半乳糖凝集素-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， 连接Dectin-1。从机制上讲，我们发现肿瘤相关巨噬细胞（TAMs）中的Dectin-1信号转导 诱导其重编程为免疫抑制性M2样巨噬细胞，导致Th 2和Treg 体内CD 4 + T细胞的分化。基于这些数据，我们假设半乳糖凝集素-9的Dectin-1连接是 驱动胰腺TME中免疫抑制的枢轴开关。在目标1中，我们将确定 在PDA中Dectin-1激活的后果，并测试靶向Dectin-1或半乳糖凝集素-9是否具有保护性， 延长多种PDA小鼠模型的存活率。我们还将确定特定的隔室（上皮与 炎症），其中Dectin-1信号传导是致癌的。在目标2中，我们将测试我们的首要假设是， 骨髓细胞Dectin-1信号转导诱导免疫抑制性巨噬细胞亚群的差异扩增 其具有产生导致肿瘤容许性无反应性的促肿瘤发生T细胞的倾向。我们也将 描述了PDA中Dectin-1依赖性适应性免疫无能的生化机制，并测试了我们的 翻译假说，靶向Dectin-1将与检查点受体定向的 免疫方案。总的来说，目标2将定义Dectin的细胞和生化机制， 1促进PDA的发展，并为开发新的实验治疗策略提供指导。 目的3将致力于阐明Dectin-1信号在人PDA中的免疫抑制作用， 研究Dectin-1-Galectin-9轴对获得性免疫抑制和临床的影响， 患者的病理疾病特征和结果。我们预计，通过半乳糖凝集素-9激活Dectin-1是一种有效的方法。 PDA中免疫抑制性骨髓细胞编程的主要驱动因素，导致CD 4+和CD 8 + T细胞无反应性。 我们相信我们的工作具有很高的翻译价值，并将表明Dectin-1和Galectin-9可能具有吸引力 用于患者的实验性治疗。而且，这项工作很可能对一个角色产生深远的影响 Dectin-1在其他癌症亚型和无菌性炎症中的作用。

项目成果

Targeting the Atf7ip-Setdb1 Complex Augments Antitumor Immunity by Boosting Tumor Immunogenicity.

• DOI: 10.1158/2326-6066.cir-21-0543
• 发表时间: 2021-11
• 期刊: CANCER IMMUNOLOGY RESEARCH
• 影响因子: 10.1
• 作者: Hu, Hai;Khodadadi-Jamayran, Alireza;Dolgalev, Igor;Cho, Hyunwoo;Badri, Sana;Chiriboga, Luis A.;Zeck, Briana;Gregorio, Miguel Lopez De Rodas;Dowling, Catriona M.;Labbe, Kristen;Deng, Jiehui;Chen, Ting;Zhang, Hua;Zappile, Paul;Chen, Ze;Ueberheide, Beatrix;Karatza, Angeliki;Han, Han;Ranieri, Michela;Tang, Sittinon;Jour, George;Osman, Iman;Sucker, Antje;Schadendorf, Dirk;Tsirigos, Aristotelis;Schalper, Kurt A.;Velcheti, Vamsidhar;Huang, Hsin-yi;Jin, Yujuan;Ji, Hongbin;Poirier, John T.;Li, Fei;Wong, Kwok-Kin
• 通讯作者: Wong, Kwok-Kin