Myeloid suppressor cell-associated immune dysfunction in CSA1M fibrosarcoma tumor-bearing mice.

CSA1M tumor-bearing mice exhibited a severe immune dysfunction but the underlying mechanism remained unclear. In this study, we demonstrated that the myeloid suppressor cell (Mac-1(+)Gr-1(+) cells)-(MSC) related T cell immunosuppression in this tumor-bearing model. In mice at the late stage of CSA1M tumor-bearing (Late TB [8-10 weeks after cell inoculation in male BALB/c mice]), the percentages for CD4(+) and CD8(+) T cells decreased but Mac-1(+) cells increased in spleens with severe splenomegaly. There was no deficit for concanavalin A-induced CD4(+) and CD8(+) T cell proliferation, interferon-gamma (IFN-gamma) and interleukin (IL)-4 production, but delayed-type hypersensitivity reaction were attenuated. Analysis of cytokine production in unfractionated spleen cells showed a significant reduction of IFN-gamma and a marked increase of IL-10 and IL-4. In Late-TB mice, splenic MSC number intensively accumulated; the mRNA expressions of the signal transducer and activator of transcription 1, interferon regulatory factor 1 (IRF-1), and inducible nitric-oxide synthase (iNOS) were enhanced in MSC; the nitric oxide production and arginase enzyme activity increased in MSC as well. Furthermore, the concanavalin A-induced T cell proliferation was inhibited in the presence of lipopolysaccharide- or IFN-gamma-activated MSC from Late-TB mice, which could be reversed by the iNOS specific inhibitor L-NMMA. iNOS seemed to be required more than arginase for the suppressive activity of MSC. Taken together, our results suggest that the immune dysfunction in tumor-bearing mice might be causally associated with the accumulation of MSC and its tumor-favoring property.