title: Characterization of myeloid leukocytes and soluble mediators in pancreatic cancer: importance of myeloid-derived suppressor cells.
abstract: Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. PDAC cells activate tumor-specific immune responses but simultaneously trigger a strong immunosuppression. We showed that PDAC cells produce high amount of chronic inflammatory mediators and PDAC tumors build an immunosuppressive cytokine milieu, which correlates with tumor progression. We observed a low frequency of dendritic cells (DC) and a pronounced accumulation of macrophages and myeloid-derived suppressor cells (MDSC) in murine PDAC tumors. A strong accumulation of MDSC has also been demonstrated in the peripheral blood of resected PDAC patients. While DC and macrophages seem not to play a significant role in this PDAC model in the context of immunosuppression, MDSC are highly suppressive, and their accumulation is associated with an increase in intratumoral VEGF concentration during the PDAC progression. Application of the phosphodiesterase-5 inhibitor sildenafil led to a prolonged survival of PDAC-bearing female mice, which was due to the decrease in MDSC frequencies and in the systemic VEGF level. This led to a restoration of anticancer immune responses, manifested in the recovery of T lymphocyte functions and in an increase in the frequency of conventional CD4+T cells in tumors and IFNγ level in serum of PDAC-bearing mice. Thus, MDSC are strongly involved in the PDAC-associated immunosuppression and that their depletion could create new approaches for therapy of PDAC.
authors.affiliation: Department of General Surgery; University of Heidelberg ; Heidelberg, Germany.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Karakhanova
authors.affiliation: Department of General Surgery; University of Heidelberg ; Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Link
authors.affiliation: Department of General Surgery; University of Heidelberg ; Heidelberg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Heinrich
authors.affiliation: Department of General Surgery; University of Heidelberg ; Heidelberg, Germany ; Skin Cancer Unit; German Cancer Research Center (DKFZ) ; Heidelberg and Department of Dermatology; Venereology and Allergology ; University Medical Center Mannheim; University of Heidelberg ; Heidelberg, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Shevchenko
authors.affiliation: Department of General Surgery; University of Heidelberg ; Heidelberg, Germany ; Cancer Center; Union Hospital ; Tongji Medical College; Huazhong University of Science and Technology ; Wuhan, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of General Surgery; University of Heidelberg ; Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hassenpflug
authors.affiliation: Department of General Surgery; University of Heidelberg ; Heidelberg, Germany.
authors.forename: Henriette
authors.initials: H
authors.lastname: Bunge
authors.affiliation: Department of General Surgery; University of Heidelberg ; Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: von Ahn
authors.affiliation: Department of General Surgery; University of Heidelberg ; Heidelberg, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Brecht
authors.affiliation: Department of General Surgery; University of Heidelberg ; Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mathes
authors.affiliation: Department of General Surgery; University of Heidelberg ; Heidelberg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Maier
authors.affiliation: Skin Cancer Unit; German Cancer Research Center (DKFZ) ; Heidelberg and Department of Dermatology; Venereology and Allergology ; University Medical Center Mannheim; University of Heidelberg ; Heidelberg, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
authors.affiliation: Department of General; Visceral, and Transplant Surgery ; Ludwig-Maximilians-University Munich ; Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Werner
authors.affiliation: Department of General; Visceral, and Transplant Surgery ; Ludwig-Maximilians-University Munich ; Germany.
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Bazhin
keywords: ARG-1, arginase-1; DC, dendritic cells; MDSC; MDSC, myeloid-derived suppressor cells; NO, nitric oxide; PDAC, pancreatic ductal adenocarcinoma; TIL, tumor-infiltrating leukocytes; Tregs, regulatory T cells; immune suppression; orthotopic Panc02 model; pancreatic adenocarcinoma