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

摘要 胰腺导管腺癌(PDA)是一种侵袭性疾病，存活率低。胰腺的进展 肿瘤的发生需要免疫抑制炎症与致癌基因突变协同作用。然而， PDA中促肿瘤炎症的驱动因素知之甚少。Dectin-1是C型凝集素的一员 模式识别受体家族，是对真菌病原体的先天免疫反应所必需的。然而， Dectin-1在无菌炎症或促进肿瘤发生方面没有既定的作用。非病原体- 衍生的Dectin-1配体还没有得到很好的表征。我们的初步数据显示Dectin-1在 在小鼠和人的PDA的炎症和上皮室中都有表达。此外，Dectin-1 结扎促进了PDA的发展，而Dectin-1的缺失则具有保护作用。此外，我们发现， Galectin-9是一种与β-半乳糖苷有亲和力的凝集素，广泛存在于pda肿瘤微环境中。 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 诱导它们重新编程为免疫抑制的M2样巨噬细胞，导致Th2和Treg 体内CD4+T细胞的分化。根据这些数据，我们推测Galectin-9的Dectin-1连接是 在胰腺TME中驱动免疫抑制的关键开关。在目标1中，我们将确定 PDA中Dectin-1激活的后果并测试靶向Dectin-1或Galectin-9是否具有保护性和 延长不同PDA小鼠模型的存活时间。我们还将确定特定的隔室(上皮VS 炎性)，其中Dectin-1信号是致癌的。在目标2中，我们将测试我们的压倒一切的假设 髓系细胞中的Dectin-1信号诱导免疫抑制巨噬细胞亚群的差异性扩张 它们具有产生促肿瘤T细胞的倾向，从而导致肿瘤容许性无能。我们也会 阐明PDA依赖Dectin-1的获得性免疫无能的生化机制 靶向Dectin-1的翻译假说与检查点受体导向的协同效应 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。 目的3将致力于阐明Dectin-1信号在人PDA和PDA中的免疫抑制作用 探讨Dectin-1-Galectin-9轴在抑制获得性免疫中的意义及临床意义 患者的病理疾病特征和转归。我们预计通过Galectin-9激活Dectin-1是一种 PDA中免疫抑制髓系细胞编程导致CD4+和CD8+T细胞无能的主要驱动因素。 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 对患者进行实验性治疗的靶点。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。

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.