Gemcitabine reduces MDSCs, tregs and TGFβ-1 while restoring the teff/treg ratio in patients with pancreatic cancer

Abstract

BackgroundCancer immunotherapy can be potentiated by conditioning regimens such as cyclophosphamide, which reduces the level of regulatory T cells (tregs). However, myeloid suppressive cells are still remaining. Accordingly to previous reports, gemcitabine improves immune status of cancer patients. In this study, the role of gemcitabine was further explored to map its immunological target cells and molecules in patients with pancreatic cancer.MethodsPatient blood was investigated by flow cytometry and cytokine arrays at different time points during gemcitabine treatment.ResultsThe patients had elevated myeloid-derived suppressor cells (MDSCs), and Tregs at diagnosis. Myeloid cells were in general decreased by gemcitabine. The granulocytic MDSCs were significantly reduced while monocytic MDSCs were not affected. In vitro, monocytes responding to IL-6 by STAT3 phosphorylation were prevented to respond in gemcitabine medium. However, gemcitabine could not prevent STAT3 phosphorylation in IL-6-treated tumor cell lines. TGFβ-1 was significantly reduced after only one treatment and continued to decrease. At the same time, the effector T cell:Treg ratio was increased and the effector T cells had full proliferative capacity during the gemcitabine cycle. However, after a resting period, the level of suppressor cells and TGFβ-1 had been restored showing the importance of continuous conditioning.ConclusionsGemcitabine regulates the immune system in patients with pancreatic cancer including MDSCs, Tregs and molecules such as TGFβ-1 but does not hamper the ability of effector lymphocytes to expand to stimuli. Hence, it may be of high interest to use gemcitabine as a conditioning strategy together with immunotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1037-z) contains supplementary material, which is available to authorized users.

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

“…Low dose chemotherapy has been shown to be effective in eliminating MDSC populations in tumour-bearing mice; treatments with chemotherapy such as 5-fluorouracil (5FU), paclitaxel, cisplatin, and gemcitabine were found to deplete MDSCs and enhance anti-tumour immune activity [200][201][202][203]. However, a contrasting effect in the use of chemotherapy against MDSC was observed where MDSCs were transiently induced following cyclophosphamide treatment in tumour-bearing mice and patients [204,205].…”

Strategies for Increasing Pancreatic Tumor Immunogenicity

“…It is also possible that vaccines upregulate multiple immune escape mechanisms, and elucidation of these would be necessary to ensure vaccine efficacy. As chemotherapy transiently depletes suppressive Tregs in PDAC patients (37–39), chemotherapy should be considered in addition to administration of an immunomodulatory agent to attempt to overcome the potent immunosuppressive TME.…”

“…(Table 1). Gemcitabine-based chemotherapy is often used as the chemotherapy backbone in these combination immunotherapy trials because it has been shown to increase tumor antigen availability, and transiently deplete immunosuppressive Tregs and myeloid derived suppressor cells (MDSC) in the PDAC TME (37–39,126). Lower numbers of intratumoral Tregs are associated with increased disease free survival after pancreatectomy (30), suggesting that Treg accumulation is an important determinant of survival in patients with PDAC.…”

“…In phase II studies, gemcitabine based therapy synergizes with IDO inhibition to improve response rates in PDAC (133), possibly via transient depletion of Tregs (39). This provides an immune system reset, allowing for chemotherapy-mediated elimination of previously activated Tregs, followed by indoximod mediated inhibition of subsequent Treg activation.…”

Distinct chemotherapy‐associated anti‐cancer immunity by myeloid cells inhibition in murine pancreatic cancer models

“…In our intraperitoneal‐dissemination and liver‐metastasis PDAC mice models, GEM treatment decreased numbers of myeloid cells and increased CD4+ and CD8+ cells. In other cancer mice model, GEM was proven to be suppressive to myeloid‐lineage cells, especially, myeloid‐derived suppressor cells . Additionally, in BALB/c mice system, GEM depleted B‐lymphocytes; in contrast, tumor‐specific CD4+ and CD8+ cells were augmented .…”