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.
Highlights
Cancer immunotherapy can be potentiated by conditioning regimens such as cyclophosphamide, which reduces the level of regulatory T cells
Patient characteristics In this study, ten patients diagnosed with pancreatic adenocarcinoma were enrolled to receive gemcitabine treatment as their standard of care and were investigated for their immune profile before and at different time points post treatment initiation
We investigated the immunomodulatory properties of gemcitabine chemotherapy in ten pancreatic cancer patients
Summary
Cancer immunotherapy can be potentiated by conditioning regimens such as cyclophosphamide, which reduces the level of regulatory T cells (tregs). MDSCs are expanded and activated in response to a variety of inflammatory factors that are secreted directly by tumor cells, PSCs and other adjacent immune cells. MDSCs are able to suppress the immune response mainly in two ways: They either directly suppress T cell responses or induce the expansion of regulatory T cells (Tregs). Both MDSCs and Tregs are present in early and late stage pancreatic tumors, whereas tumor-specific T cells are low in numbers and have an impaired activation [6]. MDSCs and Tregs were found to be positively and negatively correlated with tumor progression and overall survival, respectively [7, 8]
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