Expansion of Spleen Myeloid Suppressor Cells Represses NK Cell Cytotoxicity in Tumor Bearing Host (49.13)

Abstract

Abstract Tumor growth promotes the expansion of myeloid suppressor cells. An inverse correlation between natural killer (NK) cell activation and myeloid suppressor cell expansion in tumor-bearing patients and mice prompted us to investigate the role of myeloid suppressor cells in controlling NK cell antitumor cytotocixity. In TS/A breast tumor model, the in vivo NK cell cytotoxicity was impaired in tumor-bearing mice. After adoptive transfer to naive recipients, CD11b+Gr-1+ myeloid suppressor cells freshly isolated from spleens of tumor-bearing mice but not naive mice were able to inhibit NK cell cytotoxicity. An in vivo imaging analysis indicated that the removal of tumors resulted in a significant increase in NK cell cytotoxicity in lung to eliminate injected YAC-1 cells. FACS analysis of the composition of lung leucocytes further indicated that the removal of tumors also lead to the reduction of CD11b+Gr-1+ myeloid suppressor cells accumulated in the lung. These data suggest that CD11b+Gr-1+ myeloid suppressor cells suppress NK cell cytotoxicity. The inhibition of NK cell cytotoxicity is cell-cell contact dependent. Inhibition of perforin but not granzyme B was responsible for myeloid suppressor cell-mediated inhibition of NK cell cytotoxicity. Western blot analyses further suggested that myeloid suppressor cells suppress IL-2 mediated NK cell cytotoxicity by affecting the activity of Stat5.