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Metzger, P.* ; Kirchleitner, S.V.* ; Boehmer, D.F.R.* ; Hörth, C.* ; Eisele, A.* ; Ormanns, S.* ; Gunzer, M.* ; Lech, M.* ; Lauber, K.* ; Endres, S. ; Duewell, P.* ; Schnurr, M.* ; König, L.M.*

Systemic but not MDSC-specific IRF4 deficiency promotes an immunosuppressed tumor microenvironment in a murine pancreatic cancer model.

Cancer Immunol. Immunother. 69, 2101–2112 (2020)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Pancreatic ductal adenocarcinoma is characterized by a strong immunosuppressive network with a dense infiltration of myeloid cells including myeloid-derived suppressor cells (MDSC). Two distinct populations of MDSC have been defined: polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC). Several factors influence the development and function of MDSC including the transcription factor interferon regulatory factor 4 (IRF4). Here, we show that IRF4 deficiency accelerates tumor growth and reduces survival, accompanied with a dense tumor infiltration with PMN-MDSC and reduced numbers of CD8(+) T cells. As IRF4 has been described to modulate myeloid cell development and function, particularly of PMN-MDSC, we analyzed its role using MDSC-specific IRF4 knockout mice with the Ly6G or LysM knock-in allele expressing Cre recombinase and Irf4(flox). In GM-CSF-driven bone marrow cultures, IRF4 deficiency increased the frequency of MDSC-like cells with a strong T cell suppressive capacity. Myeloid (LysM)-specific depletion of IRF4 led to increased tumor weight and a moderate splenic M-MDSC expansion in tumor-bearing mice. PMN cell (Ly6G)-specific depletion of IRF4, however, did not influence tumor progression or MDSC accumulation in vivo in accordance with our finding that IRF4 is not expressed in PMN-MDSC. This study demonstrates a critical role of IRF4 in the generation of an immunosuppressive tumor microenvironment in pancreatic cancer, which is independent of IRF4 expression in PMN-MDSC.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Myeloid-derived Suppressor Cells (mdsc) ; Irf4 ; Immunosuppression ; Pancreatic Cancer ; Myelopoiesis; Suppressor-cells; Dendritic Cells; Neutrophil; Differentiation; Expansion; Survival
ISSN (print) / ISBN 0340-7004
e-ISSN 1432-0851
Zeitschrift Cancer Immunology, Immunotherapy
Quellenangaben Band: 69, Heft: , Seiten: 2101–2112 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort One New York Plaza, Suite 4600, New York, Ny, United States
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Unit for Clinical Pharmacology (KKG-EKLiP)