Dissecting the source and mechanisms of IL-17-mediated modulation of pancreatic tumorigenesis

摘要 胰腺癌（PDAC）的发病率稳步上升，而大多数治疗方式 仍然无效。因此，得知PDAC是癌症的四大原因之一并不奇怪- 相关死亡率。这种恶性肿瘤最引人注目的是，即使在早期发现， 仍然贫穷。众所周知，胰腺癌的特征在于免疫抑制环境， 已经发现周围的癌前病变或胰腺上皮内瘤变（PanIN）， 被认为是对大多数治疗缺乏反应的主要原因之一。然而，监管信号 在这种抑制性TME的发展之前和支持这种发展的TME没有得到很好的表征。的目标 这项赠款是为了表征的机制和监管机构牵连的产生， 免疫抑制性TME，其表征胰腺肿瘤发生过程，并通过 药理学和微生物干预。我们的实验室发现，分泌IL-17的免疫细胞在免疫系统中起着重要的作用。 在基因工程小鼠（GEMM）模型中促进胰腺肿瘤发生的重要作用 胰腺癌我们现在计划描述IL-17促进肿瘤发生的机制， 使用GEMM从胰腺致癌上皮特异性地遗传缺失IL-17受体，和 CRISPR/Cas9（Aim 1）.我们还发现，IL-17中和减少了骨髓细胞的募集，主要是 中性粒细胞，并诱导CD 8 +T细胞活化和PDAC原位模型。单克隆抗体 IL-17或嗜中性粒细胞将用于评估IL-17所采用的机制，其支持了 免疫抑制性TME（目的2）。最后，我们最近发现，粪便微生物移植可以调节 全身性肿瘤特别地，人PDAC相关的肠道细菌能够增加小鼠中的IL-17水平。 循环，这可能会影响胰腺癌等远处肿瘤。我们现在计划明确地解决 肠道细菌促进Th 17分化及其系统性意义 微生物移植（目标3）。实现我们的目标不仅有助于我们更好地了解免疫学， 作为胰腺肿瘤发生中涉及的微生物机制，但也将导致实际的新的 单克隆抗体、窄谱抗生素或微生物移植的干预措施， 对预防和/或治疗这种致命疾病有直接影响。

Abstract The incidence of pancreatic adenocarcinoma (PDAC) is steadily increasing while most treatment modalities remain ineffective. Therefore, it would not be a surprise to learn that PDAC is one of the top-4 causes of cancer- related mortality. What is most striking about this malignancy is that even if detected at early stages, outcomes remain poor. It is well known that pancreatic cancer is characterized by an immunosuppressive environment, already found surrounding premalignant lesions or pancreatic intraepithelial neoplasia (PanIN), which has been postulated as one of the main reasons for the lack of response to most therapies. However, the regulatory signals that precede and support the development of this suppressive TME are not well characterized. The objective of this grant is to characterize the mechanisms and regulators implicated in the generation of the immunosuppressive TME that characterizes pancreatic tumorigenic process and to reverse it through pharmacological and microbial interventions. Our laboratory found that IL-17-secreting immune cells play an important role in promoting pancreatic tumorigenesis in genetically engineered mouse (GEMM) models of pancreatic cancer. We now plan to characterize the mechanisms by which IL-17 promotes tumorigenesis by genetically deleting the IL-17 receptor specifically from the pancreatic oncogenic epithelium using GEMM and CRISPR/Cas9 (Aim 1). We also found that IL-17 neutralization decreases recruitment of myeloid cells, mostly neutrophils, and induces CD8+T cells activation and in PDAC orthotopic model. Monoclonal antibodies against IL-17 or neutrophils will be used to assess the mechanisms employed by IL-17 supporting an immunosuppressive TME (Aim 2). Finally, we have recently found that fecal microbial transplants can modulate tumors systemically. In particular, human PDAC-associated gut bacteria is capable of increasing IL-17 levels in circulation, which may affect distant tumors like pancreatic cancer. We now plan to definitively address the role gut bacteria in promoting Th17 differentiation and its systemic implications by performing human-into-mice fecal microbial transplants (Aim 3). Achieving our goals will not only help us better understand immunological as well as microbial mechanisms implicated in pancreatic tumorigenesis, but will also result in practical novel interventions with either monoclonal antibodies, narrow spectrum antibiotics or microbial transplants that would have a direct impact in preventing and/or treating this deadly disease.