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

• DOI: 10.1007/s00262-020-02605-9
• Publication Date: 2020-05-24T17:02:14Z
• Authors: Philipp Metzger; Sabrina V. Kirchl...; Daniel F. R. Boehmer; Christine Hörth; Angelika Eisele; Steffen Ormanns; Matthias Gunzer; Maciej Lech; Kirsten Lauber; Stefan Endres; Peter Duewell; Max Schnurr; Lars M. König
• Keywords: IRF4; Myeloid-derived Suppressor Cell; Tumor progression

Pancreatic ductal adenocarcinoma is characterized by a strong immunosuppressive network with dense infiltration of myeloid cells including myeloid-derived suppressor (MDSC). Two distinct populations MDSC have been defined: polymorphonuclear (PMN-MDSC) and monocytic (M-MDSC). Several factors influence the development function transcription factor interferon regulatory 4 (IRF4). Here, we show that IRF4 deficiency accelerates tumor growth reduces survival, accompanied PMN-MDSC reduced numbers CD8+ T cells. As has described to modulate cell function, particularly PMN-MDSC, analyzed its role using MDSC-specific knockout mice Ly6G or LysM knock-in allele expressing Cre recombinase Irf4flox. In GM-CSF-driven bone marrow cultures, increased frequency MDSC-like suppressive capacity. Myeloid (LysM)-specific depletion led weight moderate splenic M-MDSC expansion in tumor-bearing mice. PMN (Ly6G)-specific IRF4, however, did not progression accumulation vivo accordance our finding expressed PMN-MDSC. This study demonstrates critical generation an microenvironment pancreatic cancer, which independent expression