IFN-(a) Producing T Cells Contribute To The Unwanted High Proportion Of Myeloid Derived Suppressor Cells After Cyclophosphamide Treatment

MDSCs are a heterogeneous population comprising different myeloid cells at early stage of differentiation which mainly includes immature monocytes and immature granulocytes. So MDSCs can be devided into two subsets:polymorphonuclear granulocytic MDSCs (PMN-MDSCs) and monocytic MDSCs (MO-MDSC). In pathological status such as tumor,chronic infection,trauma and stress, MDSCs often accumulate in bone marrow,spleen,lymphod and the original region of disease.In tumor patient, the abundant accumulation of MDSCs in the locus mentioned above due to the many cytokines such as VEGF,GM-CSF and IL-6 which secreted by tumor cells in the develop process of tumor. The abundant accumulated cells can suppress the function of T cells by producing Arginase 1, iNOS and also by secreting suppressive cytokine TGF-β. This suppressive function of MDSCs helps tumor cells to escape the recognition and attack by immune system. What is more, MDSCs can secret metalloprotease-9 (MMP-9) and metalloprotease-13 (MMP-13) which can promote the angiogenesis and the invasion and metastasis of tumor. In a word, MDSCs facilitate the development of tumor.As a DNA alkylating agent that can kill tumor cells directly, CTX has been widely used as a chemotherapeutic drug. However, many studies reported that Using cyclophosphamide (CTX) as a chemotherapeutic drug to treat tumor patients can result in a surprising even higher proportion of myeloid derived suppressor cells (MDSCs) in their bone marrow, spleens and blood than the tumor patients that did not receive CTX treatment. This phenomenon was also viewed in tumor mice model. Obviously, this phenomenon contradicts to its antitumor effect of CTX since MDSCs are in favor of tumor development.Here we sought to clarify the mechanism of this unwanted contradictory consequence by comparing the differences of immune profiles between the CTX treated tumor bearing mice and non CTX treated tumor bearing mice. Then we found that both CD4+T cells and CD8+T cells in tumor bearing mice underwent an expansion and activation phase before the increased proportion of MDSCs in the early period of CTX treatment. Then the developed CD4+T cells and CD8+T cells released a high level of IFN-y and resulted in a high concentration IFN-y in the body. Then we did the same experiment in null mice lacking of T cells and found that in the early period, the concentration IFN-y in the CTX treated tumor null mice showed no significant differences when compared to the tumor null mice that did not received CTX treatment and in the followed period, the proportion of MDSCs in bone marrow, spleen and blood in the CTX treated tumor null mice were similar to the tumor null mice that did not received CTX treatment. In vitro, the co-culture experiment of MDSCs and T cells also proved that T cells could facilitate the expansion and survival of MDSCs and this function was mediated by IFN-y. In conclusion, our experiment proved that CTX treatment could induce the activation and proliferation of T cells which then produced a large quantity of IFN-y and the very high concentration of IFN-y induced MDSCs to reached an further higher proportion. This result gave an explanation of the unwanted consequence that CTX treatment induced and implied methods that would be applied to eliminate the bad side of CTX treatment so as to make it cure tumors more effectively.