Subtype-associated complexity and prognostic significance of the NLRP3 inflammasome landscape in pancreatic neoplasms

Abstract

Intraductal papillary mucinous neoplasm (IPMN) can progress into malignant pancreatic cancer, posing challenges in accurately assessing the risk of malignancy. While the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome pathway's role in pancreatic ductal adenocarcinoma (PDAC) has been extensively studied, its implications in IPMN remain unexplored. This study aimed to investigate the prognostic significance of NLRP3 inflammasome-related proteins across IPMN subtypes and their associations with tumor characteristics, with a secondary focus on comparing expression patterns in IPMN and PDAC. A cohort of 187 patients (100 IPMN and 87 PDAC) underwent high-dimensional histopathological imaging using the multiplexed immunohistochemical consecutive staining on single slide method and a semi-automated image analysis workflow. Expression levels of NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), caspase-1, interleukin-1 beta, interleukin-18 (IL-18), interleukin-1 receptor antagonist, and interleukin-18 binding protein (IL-18BP) were evaluated and compared between IPMN and PDAC samples. The relationships between protein expression and tumor characteristics were examined. Principal component analysis distinguished between intestinal and nonintestinal clusters based on NLRP3-associated proteins. Lower IL-18 expression was linked to the intestinal subtype, while higher caspase-1 was linked to the pancreatobiliary subtype. Elevated caspase-1 and ASC expression were associated with invasiveness in IPMN. No significant correlation was found between the examined proteins and later-stage tumor characteristics in invasive cases. The IL-18/IL-18BP ratio was an independent prognostic factor in invasive IPMN. Our findings highlight the prognostic significance of IL-18 and the IL-18/IL-18BP ratio in invasive IPMNs. These results point to a complex regulation of NLRP3 inflammasome proteins, especially effector cytokines, in pancreatic neoplasms, which are strongly linked to subtype and prognosis.