Metformin boosts antitumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study

Abstract Background Beyond demographic and immune factors, metabolic considerations, particularly metformin’s recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient survival and its potential correlation...

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Published in:JNCI : Journal of the National Cancer Institute 2024-08, Vol.116 (8), p.1374-1383
Main Authors: van Eijck, Casper W F, Vadgama, Disha, van Eijck, Casper H J, Wilmink, Johanna W, Lips, Daan J, van der Harst, Erwin, Kazemier, Geert, Patijn, Gijs A, de Hingh, Ignace H, Wijsman, Jan H, Erdmann, Joris I, Festen, Sebastiaan, Koerkamp, Bas Groot, Mieog, J Sven D, den Dulk, Marcel, Stommel, Martijn W J, Busch, Olivier R, de Wilde, Roeland F, de Meijer, Vincent E, te Riele, Wouter, Molenaar, I Quintus, Draaisma, Werner, Manusama, Eric, Lutchman, Kishan R D, van Dieren, Susan, Vlijm, Anniek, Bonsing, Bert A, Nio, C Yung, de Groot, Derik-Jan, Gootjes, Elske C, van Veldhuisen, Eran, Wit, Fenny, Daams, Freek, Cirkel, Geert, van Tienhoven, Geertjan, van Hellemond, Irene E G, de Vos-Geelen, Judith, Bosscha, Koop, Mekenkamp, Leonie J, Nijkamp, Maarten W, Los, Maartje, van der Kolk, Marion B, Homs, Marjolein, Ramaekers, Mark, Liem, Mike S, Wumkes, Miriam L, Michiels, Nynke, van Dam, Ronald, Theijse, Rutger T, Luelmo, Saskia, Bollen, Thomas L, Neumann, Ulf, Nieuwenhuijs, Vincent
Format: Article
Language:English
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Early Career Investigator Research
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Summary:Abstract Background Beyond demographic and immune factors, metabolic considerations, particularly metformin’s recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient survival and its potential correlation with distinct immune profiles in pancreatic ductal adenocarcinoma (PDAC) tumors. Methods We included 82 upfront resected and 66 gemcitabine-based neoadjuvant chemoradiotherapy (nCRT)-treated patients from the PREOPANC randomized controlled trial (RCT). Transcriptomic NanoString immunoprofiling was performed for a subset of 96 available resected specimens. Results Disparities in survival outcomes and immune profiles were apparent between metformin and non-metformin users in upfront resected patients but lacking in nCRT-treated patients. Compared to non-metformin users, upfront resected metformin users showed a higher median overall survival (OS) of 29 vs 14 months and a better 5-year OS rate of 19% vs 5%. Furthermore, metformin use was a favorable prognostic factor for OS in the upfront surgery group (HR = 0.56; 95% CI = 0.32 to 0.99). Transcriptomic data revealed that metformin users significantly underexpressed genes related to pro-tumoral immunity, including monocyte to M2 macrophage polarization and activation. Furthermore, the relative abundance of anti-inflammatory CD163+ MRC1+ M2 macrophages in non-metformin users and immune-activating CD1A+ CD1C+ dendritic cells in metformin users was heightened (P < .001). Conclusion This study unveils immune profile changes resulting from metformin use in upfront resected pancreatic cancer patients, possibly contributing to prolonged survival outcomes. Specifically, metformin use may decrease the abundance and activity of pro-tumoral M2 macrophages and increase the recruitment and function of tumor-resolving DCs, favoring antitumor immunity. [PREOPANC trial EudraCT: 2012-003181-40]
ISSN:0027-8874
1460-2105
1460-2105
DOI:10.1093/jnci/djae070