| Myeloid-derived suppressor cells (MDSCs) are widely studied, however, little is known about their tumor-associated expansion dynamics. We report MDSCs expansion, trafficking, proliferation, and survival, together with molecular regulators' profile and effects on T-cell cellularity, function, and proliferation in mammary tumor-bearing (TB) mice. MDSCs cellularity significantly increased within the spleen, peripheral blood, bone marrow, lungs, and livers of 4T1 TB mice, but not CI66 TB mice. MDSCs frequency inversely correlated with CD3+ T-cells frequency in the spleen, and peripheral blood of 4T1 TB mice, together with a significant decrease in splenic and non-parenchymal cells' IFN-gamma and IL-12, and increased IL-10, IL-13, GM-CSF, G-CSF, SCF, VEGF-A, ARG-1 and NOS-2 mRNA levels. The highest numbers of dividing MDSCs were observed in the sub-capsular region of spleens in 4T1 TB mice, with an extensive MDSC reservoir within the splenic red pulp. A significantly increased peripheral homeostatic T-cell proliferation was observed in 4T1 TB mice. Adoptive transfer of in vitro CFSE-labeled splenocytes from 4T1 TB mice into naive mice showed that MDSCs arrested mainly in the lungs after one hour; while the majority survived within the spleen at 72 hours. However, within 4T1 TB mice, MDSCs arrested and survived mainly in the spleen at one hour and 72 hours with a significantly increased MDSCs daughter cells at 72 hours in the spleen. mRNA differential expression levels of hematopoietic growth factors (GFs) modulate MDSCs' proliferation and survival within spleen versus tumor tissue. Sunitinib treatment in FVB-neuN transgenic mice delayed tumor development, and reduced incidence and growth of tumors, together with a significant decrease in splenic MDSCs numbers. TGF-beta and NOS-2 mRNA levels in the splenocytes of Sunitinib-treated mice were down-regulated compared to untreated TB mice. Thus, under the regulation of differential GFs', enzymes', and cytokines' transcripts levels, MDSCs expansion is tumor- and organ-specific. In addition, spleens of 4T1 TB mice are the main site for MDSCs' proliferation and survival as well as T-cells' extrathymic proliferation, despite the associated decrease in T-cells' frequencies and function. Moreover, Sunitinib therapeutic effects in transgenic mice suggest a role for MDSC down-regulation in controlling and treating cancer. |
