The impact of sepsis-induced inflammation on pancreatic cancer liver metastasis

1个项目摘要 2胰腺导管腺癌(PDAC)是一种高度转移性的恶性肿瘤，是 3成人癌症相关死亡。大多数接受初次PDAC切除手术的患者稍后会 4发生致命转移，尽管术中检查证实无大转移。 病变5个。肝转移占PDAC切除后六个月内发现的复发的近一半， 6与其他转移部位相比，术后时间明显提前。几个临床和 7项实验研究表明，围手术期炎症，包括败血症等感染性并发症， 8可促进肝转移。这很耐人寻味，因为PDAC患者的细菌源性内毒素升高 9肿瘤切除时的血浆浓度。此外，PDAC患者患脓毒症的风险增加，这 10提示肿瘤与全身的沟通在一定程度上重新连接了全身免疫系统，从而导致了败血症。 11易感性。尽管有这些观察，我们目前缺乏对这种关系的机械性研究 围手术期炎症与PDAC肝转移的关系。该项目的总体目标是 13确定如何抑制促转移免疫反应以防止肝转移 14例PDAC切除和脓毒症所致炎症。明确脓毒症引起的炎症对肝脏的影响 15免疫微环境，我首先模拟了PDAC患者可能经历的围手术期炎症 16术中采用脂多糖(LPS)无菌内毒素血症模型，临床上多 17例多菌败血症盲肠结扎穿刺术(CLP)模型。我的初步数据表明 18在肝脏种植PDAC细胞之前进行CLP具有促进转移的作用。然而，内毒素挑战 19具有抗转移作用，主要表现为增加CXCL9和CXCL10的释放和自然杀伤细胞的浸润 20在早期脓毒症反应的肝脏中。因此，这种方法提供了一个令人兴奋的机会来定义如何 脂多糖诱导的脓毒症诱导抗转移级联反应，以减少肝转移。这一点的中心假设是 22项目是，确定脓毒症诱导的免疫反应如何影响肝转移将揭示关键 23种机制，可以有针对性地创造一个保护性的“抗转移利基”。为了检验这一假设，目标1将 24阐明内毒素诱导的脓毒症的抗转移信号机制，并发现潜在的 可用于减少PDAC肝转移的25个治疗靶点。目标2将检查治疗方法 26通过评估脓毒症的质量如何诱导脓毒症期间靶向转移性炎症的可能性 27免疫反应受到全身性免疫抑制的影响，这是公认的 28个PDAC。这些实验的发现将揭示围手术期炎症和 29全身免疫抑制在PDAC，并为预防性治疗的发展奠定了基础 30可降低PDAC切除患者的肝转移发生率。

1 PROJECT SUMMARY 2 Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy and the third-leading cause of 3 cancer-related death in adults. A majority of patients who undergo surgery for primary PDAC resection will later 4 develop lethal metastases, despite intra-operative examination confirming the absence of macrometastatic 5 lesions. Liver metastases constitute nearly half of recurrences detected within six months after PDAC resection, 6 which is significantly earlier in the postoperative period compared to other metastatic sites. Several clinical and 7 experimental studies have shown that perioperative inflammation, including infectious complications like sepsis, 8 can promote liver metastasis. This is intriguing because bacterial-derived endotoxin is elevated in PDAC patient 9 plasma during tumor resection. Furthermore, PDAC patients are at increased risk of developing sepsis, which 10 suggests that tumor-systemic communication in part rewires systemic immunity and, consequently, sepsis 11 susceptibility. Despite these observations, we currently lack mechanistic studies investigating the relationship 12 between perioperative inflammation and PDAC liver metastasis. The overarching objective of this project is to 13 determine how pro-metastatic immune responses can be suppressed to protect against liver metastasis during 14 PDAC resection and sepsis-induced inflammation. To define how sepsis-induced inflammation impacts the liver 15 immune microenvironment, I first modeled the perioperative inflammation that PDAC patients may experience 16 during surgery by using the lipopolysaccharide (LPS) model of sterile endotoxemia, and the more clinically 17 relevant cecal and ligation puncture (CLP) model of polymicrobial sepsis. My preliminary data demonstrates that 18 performing CLP prior to seeding PDAC cells in the liver had a pro-metastatic effect. However, LPS challenge 19 had an anti-metastatic effect marked by increased CXCL9 and CXCL10 release and natural killer cell infiltration 20 in the liver during early sepsis response. Therefore, this approach presents an exciting opportunity to define how 21 LPS-induced sepsis elicits an anti-metastatic cascade to reduce liver metastasis. The central hypothesis of this 22 project is that determining how sepsis-induced immune responses influence liver metastasis will reveal critical 23 mechanisms that can be targeted to create a protective ‘anti-metastatic niche’. To test this hypothesis, Aim 1 will 24 elucidate the anti-metastatic signaling mechanisms underpinning LPS-induced sepsis, and uncover potential 25 therapeutic targets that can be exploited to reduce PDAC liver metastasis. Aim 2 will examine the therapeutic 26 potential of targeting pro-metastatic inflammation during sepsis by evaluating how the quality of sepsis-induced 27 immune responses are impacted by systemic immunosuppression, which is a well-established hallmark of 28 PDAC. The findings of these experiments will uncover critical regulators of perioperative inflammation and 29 systemic immunosuppression in PDAC, and set the stage for the development of preventative therapies to 30 reduce the incidence of liver metastasis among resected PDAC patients.