1. Gemcitabine treatment promotes immunosuppressive microenvironment in pancreatic tumors by supporting the infiltration, growth, and polarization of macrophages.
- Author
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Deshmukh SK, Tyagi N, Khan MA, Srivastava SK, Al-Ghadhban A, Dugger K, Carter JE, Singh S, and Singh AP
- Subjects
- Cell Differentiation immunology, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Cytokines metabolism, Deoxycytidine pharmacology, Humans, Macrophage Activation immunology, Macrophages metabolism, Macrophages pathology, Pancreatic Neoplasms drug therapy, Gemcitabine, Deoxycytidine analogs & derivatives, Immunomodulation drug effects, Macrophages drug effects, Macrophages immunology, Pancreatic Neoplasms immunology, Pancreatic Neoplasms pathology, Tumor Microenvironment drug effects, Tumor Microenvironment immunology
- Abstract
Chemotherapy-induced immunosuppression poses an additional challenge to its limited efficacy in pancreatic cancer (PC). Here we investigated the effect of gemcitabine on macrophages, which are the first line of immune-defense mechanisms. We observed an increased presence of macrophages in orthotopic human pancreatic tumor xenografts from mice treated with gemcitabine as compared to those from vehicle only-treated mice. Conditioned media from gemcitabine-treated PC cells (Gem-CM) promoted growth, migration and invasion of RAW264.7 macrophage. In addition, Gem-CM also induced upregulation of M2-polarized macrophage markers, arginase-1 and TGF-β1. Cytokine profiling of gemcitabine-treated PC cells identified IL-8 as the most differentially-expressed cytokine. Incubation of Gem-CM with IL-8 neutralizing antibody diminished its ability to induce growth, migration and invasion of RAW264.7 macrophages, but did not abrogate their M2 polarization. Together, our findings identify IL-8 as an important mediator in the gemcitabine-induced infiltration of macrophages within the pancreatic tumor microenvironment and suggest the requirement of additional mechanism(s) for macrophage polarization.
- Published
- 2018
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