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

1项目概要 2胰腺导管腺癌（PDAC）是一种高度转移性恶性肿瘤，是胰腺癌的第三大病因。 3例成人癌症相关死亡。大多数接受原发性PDAC切除术的患者， 4例发生致死性转移，尽管术中检查证实不存在大转移 5处病变。肝转移占PDAC切除术后6个月内检测到的复发的近一半， 6，与其他转移部位相比，其在术后阶段明显更早。多种临床和 7实验研究表明，围手术期炎症，包括感染性并发症，如败血症， 8可促进肝转移。这是有趣的，因为PDAC患者中细菌源性内毒素升高 9例肿瘤切除术期间血浆。此外，PDAC患者发生败血症的风险增加， 10表明肿瘤-全身通讯部分重新连接全身免疫，因此，败血症 11敏感性。尽管有这些观察结果，我们目前缺乏调查这种关系的机制研究。 围手术期炎症反应与PDAC肝转移的相关性为12。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 PDAC切除术和脓毒症诱导的炎症。定义脓毒症引起的炎症如何影响肝脏 15免疫微环境，我首先对PDAC患者可能经历的围手术期炎症进行了建模 16在手术过程中通过使用脂多糖（LPS）无菌内毒素血症模型， 17多微生物脓毒症的相关盲肠和结扎穿刺（CLP）模型。我的初步数据显示， 18在肝脏中接种PDAC细胞之前进行CLP具有促转移作用。然而，LPS挑战 19具有抗转移作用，其特征在于增加CXCL 9和CXCL 10释放和自然杀伤细胞浸润 20在早期脓毒症反应期间在肝脏中。因此，这种方法提供了一个令人兴奋的机会来定义如何 21 LPS诱导的脓毒症激发抗转移级联反应以减少肝转移。这个问题的核心假设是 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的 23种机制，可以有针对性地创造一个保护性的“抗转移生态位”。为了验证这一假设，目标1将 24阐明了支持LPS诱导的脓毒症的抗转移信号传导机制，并揭示了潜在的 可用于减少PDAC肝转移的25个治疗靶点。目标2将检查治疗 26通过评估脓毒症诱导的炎症的质量， 27免疫应答受到全身免疫抑制的影响，这是免疫应答的公认标志。 28 PDAC。这些实验的结果将揭示围手术期炎症的关键调节因子， 29 PDAC中的全身免疫抑制，并为预防性治疗的发展奠定了基础， 降低PDAC患者肝转移的发生率。

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.