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

摘要 胰腺癌(PDAC)的发病率正在稳步上升，而大多数治疗方法 仍然是无效的。因此，了解到PDAC是导致癌症的四大原因之一也就不足为奇了。 相关死亡率。这种恶性肿瘤最令人震惊的是，即使在早期阶段发现，结果 继续保持贫穷。众所周知，胰腺癌的特点是免疫抑制环境， 已发现癌前病变周围或胰腺上皮内瘤变(Panin)，这已被 被认为是大多数治疗缺乏反应的主要原因之一。然而，监管信号 这些先于和支持这种抑制性TME发展的东西没有得到很好的描述。的目标是 这笔赠款是为了描述与产生 免疫抑制的TME是胰腺肿瘤发生过程的特征，并通过 药理和微生物干预。我们的实验室发现，分泌IL-17的免疫细胞在 基因工程小鼠(GEMM)在促进胰腺肿瘤发生中的重要作用 胰腺癌。我们现在计划表征IL-17促进肿瘤发生的机制，通过 使用GEMM和GEMM从胰腺致癌上皮特异性基因删除IL-17受体 CRISPR/CAS9(目标1)。我们还发现，IL-17中和减少了髓系细胞的募集，主要是 中性粒细胞，并诱导CD8+T细胞活化和在PDAC原位模型中。抗肿瘤的单抗 IL-17或中性粒细胞将被用来评估IL-17支持 免疫抑制TME(目标2)。最后，我们最近发现，粪便微生物移植可以调节 系统性的肿瘤。特别是，人类PDAC相关肠道细菌能够增加IL-17水平 循环，这可能会影响远处的肿瘤，如胰腺癌。我们现在计划明确地解决这个角色 肠道细菌促进Th17分化及其在人-鼠粪便中的系统意义 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理解免疫学 作为与胰腺肿瘤发生有关的微生物机制，但也将产生实用的新书 使用单抗、窄谱抗生素或微生物移植的干预措施 在预防和/或治疗这种致命疾病方面有直接影响。

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.