Systemic but not MDSC-specific IRF4 deficiency promotes an immunosuppressed tumor microenvironment in a murine pancreati
- PDF / 1,141,595 Bytes
- 12 Pages / 595.276 x 790.866 pts Page_size
- 29 Downloads / 169 Views
ORIGINAL ARTICLE
Systemic but not MDSC‑specific IRF4 deficiency promotes an immunosuppressed tumor microenvironment in a murine pancreatic cancer model Philipp Metzger1,2 · Sabrina V. Kirchleitner1,3 · Daniel F. R. Boehmer1 · Christine Hörth1 · Angelika Eisele4,5 · Steffen Ormanns6 · Matthias Gunzer7,8 · Maciej Lech9 · Kirsten Lauber2 · Stefan Endres1,10,11 · Peter Duewell1,12 · Max Schnurr1 · Lars M. König1 Received: 31 December 2019 / Accepted: 12 May 2020 © The Author(s) 2020
Abstract 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 C D8+ 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 knockin allele expressing Cre recombinase and Irf4flox. 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. Keywords Myeloid-derived suppressor cells (MDSC) · IRF4 · Immunosuppression · Pancreatic cancer · Myelopoiesis
Introduction The tumor microenvironment (TME) contains a variety of immune cells with opposing functions. While anti-tumoral cells such as cytotoxic T cells, T helper cells and natural killer cells are important in the immune surveillance and protection against tumors, certain immune modulatory cells including myeloid subsets shape the TME during immune Max Schnurr, Lars M. König have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02605-9) contains supplementary material, which is available to authorized users. * Max Schnurr [email protected]‑muenchen.de Extended author information available on the last page of the article
equilibrium and escape phase [1] and enhance tumor progression by dampening the effector cells [2]. Three main subsets within the myeloid compartment are characterized by a strong T cell suppressive c
Data Loading...
