Abstract 1584: The interplay between natural killer cells and pancreatic stellate cells in pancreatic ductal adenocarcinoma

Abstract Natural Killer (NK) cells have been shown to possess potent anti-tumor activity against multiple cancer types and consequently have been harnessed as a cellular cancer immunotherapy. Furthermore, targeting of pancreatic stellate cells has received increasing interest in the treatment of pancreatic ductal adenocarcinoma (PDAC), with several clinical trials testing the hypothesis that rendering activated pancreatic stellate cells/cancer associated fibroblasts (aPSC/CAF) into a quiescent state (qPSC) can enhance anticancer treatment. Despite this interest, our understanding of the interplay between these two cell types remains limited. We hypothesized that PSC/CAF may exhibit a dynamic interaction with NK cells that may be harnessed for therapeutic strategies and patient stratification. Employing a series of in vitro assays, we demonstrate a significant bi-directional interaction between natural killer cells and pancreatic stellate cells in the context of PDAC. NK cells were found to effectively target and eliminate both aPSC and qPSC, with PSC activation conferring some protection from NK-lysis. Furthermore, we highlight a significant myofibroblastic shift in PSCs regardless of previous activation status when cultured with NK cells; an interaction that was direct contact dependent. NK cells were also found to demonstrate cellular modulation of NKG2A and TIM3 in response to PSC co-culture. Drawing on Luminex ELISA analysis, we suggest that engagement of the IFN-γ signaling pathway may be driving phenotypic modulation. Global proteomic analyses demonstrated differential protein changes induced by NK cells in aPSC compared to qPSC, as well as alterations in the NK cell proteome upon such co-culture. Utilizing multiplex immunohistochemical analysis of PDAC patient samples, we highlight differential spatial distribution of phenotypically distinct NK cells and PSC/CAF subtypes in patient samples between long- (n=16) and short- (n=48) survivors. Moreover, NK-PSC proximity, and not total immune infiltrate, was found to play a prognostic role in PDAC. Our work provides a global overview of the cross-talk between NK and PSC in PDAC, demonstrating a significant bi-directional relationship which offers novel insights into potential therapeutic avenues. Furthermore, we demonstrate, for the first time to our knowledge, the prognostic role of NK-PSC proximity in patient survival and suggest its potential for patient stratification. Citation Format: Rachel Elizabeth Fincham, Parthiban Periasamy, Craig Ryan Joseph, Jia Meng, Jeffrey Chun Tatt Lim, Felicia Wee, Konstantinos Stasinos, Michelle R. Goulart, Jiangfeng Ye, Li Yen Chong, Denise Goh, Joe P. Yeong, Hemant M. Kocher. The interplay between natural killer cells and pancreatic stellate cells in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1584.