Metformin boosts antitumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study
Author:
van Eijck Casper W F12, Vadgama Disha2, van Eijck Casper H J1ORCID, Wilmink Johanna W3, , 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, Wilmink Johanna W, 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
Affiliation:
1. Department of Surgery, Erasmus University Medical Centre , Rotterdam, the Netherlands 2. Erasmus MC Cancer Institute, Erasmus University Medical Centre , Rotterdam, the Netherlands 3. Department of Medical Oncology, Amsterdam University Medical Centre , Amsterdam, the Netherlands
Abstract
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]
Funder
Survival With Pancreatic Cancer Foundation
Publisher
Oxford University Press (OUP)
Cited by
1 articles.
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