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

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 在小鼠和人类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。

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.