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Purpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses. Experimental Design: Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology–related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set. Results: Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression. Conclusions: Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.

Pancreatic cancer is one of the deadliest cancers primarily because most patients are diagnosed at advanced, unresectable stages. To reduce the incidence and mortality of pancreatic cancer, it is crucial to timely identify and optimally treat its precursors. One such precursor is intraductal papillary mucinous neoplasm (IPMN) as some of these cyst lesions have potential to progress to invasive cancer. Current clinical guidelines for predicting and treating malignant IPMN have a satisfactory sensitivity (>90%) but a dismal specificity (25-30%), leading to a number of unnecessary pancreatic resections in benign IPMN. Therefore, there is an urgent unmet need to identify molecular biomarkers to improve malignant IPMN prediction. The present study was thus conducted to identify metabolomic biomarkers that can preoperatively differentiate malignant IPMN from benign IPMN. A global plasma metabolomic analysis of 607 metabolites was performed on Xevo GS-X2 quadrupole time-of-flight (TOF) mass spectrometers (MS) using a 2D column configuration in 125 cases of low/moderate-grade IPMN and 50 cases of high-grade/invasive IPMN, confirmed by surgical pathology. Of the 607 metabolites, 19 were selected based on their p values for the differences between the two groups compared (all p Citation Format: Johannes Fahrmann, Hao Fan, Michele Yip-Schneider, Huangbing Wu, Ziyue Liu, Jun Wan, Sheng Liu, Samir Hanash, C. Max Schmidt, Jianjun Zhang. A plasma metabolomic signature improves prediction of malignant intraductal papillary mucinous neoplasm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3387.