Browsing by Subject "Carcinoma, Pancreatic Ductal"

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Open Access
Adjuvant radiotherapy in the treatment of invasive intraductal papillary mucinous neoplasm of the pancreas: an analysis of the surveillance, epidemiology, and end results registry.
(Ann Surg Oncol, 2012-04) Worni, M; Akushevich, I; Gloor, B; Scarborough, J; Chino, JP; Jacobs, DO; Hahn, SM; Clary, BM; Pietrobon, R; Shah, A
BACKGROUND: Management and outcomes of patients with invasive intraductal papillary mucinous neoplasm (IPMN) of the pancreas are not well established. We investigated whether adjuvant radiotherapy (RT) improved cancer-specific survival (CSS) and overall survival (OS) among patients undergoing surgical resection for invasive IPMN. METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry was used in this retrospective cohort study. All adult patients with resection of invasive IPMN from 1988 to 2007 were included. CSS and OS were analyzed using Kaplan-Meier curves. Unadjusted and propensity-score-adjusted Cox proportional-hazards modeling were used for subgroup analyses. RESULTS: 972 patients were included. Adjuvant RT was administered to 31.8% (n=309) of patients. There was no difference in overall median CSS or OS in patients who received adjuvant RT (5-year CSS: 26.5 months; 5-year OS: 23.5 months) versus those who did not (CSS: 28.5 months, P=0.17; OS: 23.5 months, P=0.23). Univariate predictors of survival were lymph node (LN) involvement, T4-classified tumors, and poorly differentiated tumor grade (all P<0.05). In the propensity-score-adjusted analysis, adjuvant RT was associated with improved 5-year CSS [hazard ratio (HR): 0.67, P=0.004] and 5-year OS (HR: 0.73, P=0.014) among all patients with LN involvement, though further analysis by T-classification demonstrated no survival differences among patients with T1/T2 disease; patients with T3/T4-classified tumors had improved CSS (HR: 0.71, P=0.022) but no difference in OS (HR: 0.76, P=0.06). CONCLUSION: On propensity-score-adjusted analysis, adjuvant RT was associated with improved survival in selected subsets of patients with invasive IPMN, particularly those with T3/T4 tumors and LN involvement.
Open Access
Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance.
(Nature medicine, 2017-05) Daley, Donnele; Mani, Vishnu R; Mohan, Navyatha; Akkad, Neha; Ochi, Atsuo; Heindel, Daniel W; Lee, Ki Buom; Zambirinis, Constantinos P; Pandian, Gautam Sd Balasubramania; Savadkar, Shivraj; Torres-Hernandez, Alejandro; Nayak, Shruti; Wang, Ding; Hundeyin, Mautin; Diskin, Brian; Aykut, Berk; Werba, Gregor; Barilla, Rocky M; Rodriguez, Robert; Chang, Steven; Gardner, Lawrence; Mahal, Lara K; Ueberheide, Beatrix; Miller, George
The progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of intratumoral immune tolerance are uncertain. Dectin 1 is an innate immune receptor crucial for anti-fungal immunity, but its role in sterile inflammation and oncogenesis has not been well defined. Furthermore, non-pathogen-derived ligands for dectin 1 have not been characterized. We found that dectin 1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin 1 ligation accelerated the progression of PDA in mice, whereas deletion of Clec7a-the gene encoding dectin 1-or blockade of dectin 1 downstream signaling was protective. We found that dectin 1 can ligate the lectin galectin 9 in mouse and human PDA, which results in tolerogenic macrophage programming and adaptive immune suppression. Upon disruption of the dectin 1-galectin 9 axis, CD4⁺ and CD8⁺ T cells, which are dispensable for PDA progression in hosts with an intact signaling axis, become reprogrammed into indispensable mediators of anti-tumor immunity. These data suggest that targeting dectin 1 signaling is an attractive strategy for developing an immunotherapy for PDA.
Open Access
NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma.
(The Journal of experimental medicine, 2017-06) Daley, Donnele; Mani, Vishnu R; Mohan, Navyatha; Akkad, Neha; Pandian, Gautam SD Balasubramania; Savadkar, Shivraj; Lee, Ki Buom; Torres-Hernandez, Alejandro; Aykut, Berk; Diskin, Brian; Wang, Wei; Farooq, Mohammad S; Mahmud, Arif I; Werba, Gregor; Morales, Eduardo J; Lall, Sarah; Wadowski, Benjamin J; Rubin, Amanda G; Berman, Matthew E; Narayanan, Rajkishen; Hundeyin, Mautin; Miller, George
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4⁺ T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8⁺ T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3^-/- hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.
Open Access
PPDPF Promotes the Development of Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1.
(Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2023-01) Ni, Qian-Zhi; Zhu, Bing; Ji, Yan; Zheng, Qian-Wen; Liang, Xin; Ma, Ning; Jiang, Hao; Zhang, Feng-Kun; Shang, Yu-Rong; Wang, Yi-Kang; Xu, Sheng; Zhang, Er-Bin; Yuan, Yan-Mei; Chen, Tian-Wei; Yin, Fen-Fen; Cao, Hui-Jun; Huang, Jing-Yi; Xia, Ji; Ding, Xu-Fen; Qiu, Xiao-Song; Ding, Kai; Song, Chao; Zhou, Wen-Tao; Wu, Meng; Wang, Kang; Lui, Rui; Lin, Qiu; Chen, Wei; Li, Zhi-Gang; Cheng, Shu-Qun; Wang, Xiao-Fan; Xie, Dong; Li, Jing-Jing
The guanine nucleotide exchange factor (GEF) SOS1 catalyzes the exchange of GDP for GTP on RAS. However, regulation of the GEF activity remains elusive. Here, the authors report that PPDPF functions as an important regulator of SOS1. The expression of PPDPF is significantly increased in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and recurrence of PDAC patients. Overexpression of PPDPF promotes PDAC cell growth in vitro and in vivo, while PPDPF knockout exerts opposite effects. Pancreatic-specific deletion of PPDPF profoundly inhibits tumor development in KRAS^G12D -driven genetic mouse models of PDAC. PPDPF can bind GTP and transfer GTP to SOS1. Mutations of the GTP-binding sites severely impair the tumor-promoting effect of PPDPF. Consistently, mutations of the critical amino acids mediating SOS1-PPDPF interaction significantly impair the GEF activity of SOS1. Therefore, this study demonstrates a novel model of KRAS activation via PPDPF-SOS1 axis, and provides a promising therapeutic target for PDAC.