Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species.
Tumor growth is associated with the accumulation of immature myeloid cells (ImC), which in mice are characterized by the expression of Gr-1 and CD11b markers. These cells suppress Ag-specific CD8+ T cells via direct cell-cell contact. However, the mechanism of immunosuppressive activity of tumor-derived ImC remains unclear. In this study we analyzed the function of ImC isolated from tumor-free control and tumor-bearing mice. Only ImC isolated from tumor-bearing mice, not those from their control counterparts, were able to inhibit the Ag-specific response of CD8+ T cells. ImC obtained from tumor-bearing mice had significantly higher levels of reactive oxygen species (ROS) than ImC isolated from tumor-free animals. Accumulation of H2O2, but not superoxide or NO, was a major contributor to this increased pool of ROS. It appears that arginase activity played an important role in H2O2 accumulation in these cells. Inhibition of ROS in ImC completely abrogated the inhibitory effect of these cells on T cells, indicating that ImC generated in tumor-bearing hosts suppress the CD8+ T cell response via production of ROS. Interaction of ImC with Ag-specific T cells in the presence of specific Ags resulted in a significant increase in ROS production compared with control Ags. That increase was independent of IFN-gamma production by T cells, but was mediated by integrins CD11b, CD18, and CD29. Blocking of these integrins with specific Abs abrogated ROS production and ImC-mediated suppression of CD8+ T cell responses. This study demonstrates a new mechanism of Ag-specific T cell inhibition mediated by ROS produced by ImCs in cancer.
Kusmartsev
Sergei
S
H. Lee Moffitt Cancer Center, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Nefedova
Yulia
Y
Yoder
Daniel
D
Gabrilovich
Dmitry I
DI
D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000502:physiology*; D005260:Female; D006098:Granulocytes; D007165:Immunosuppression Therapy; D007519:Isoantigens / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D009368:Neoplasm Transplantation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012513:Sarcoma, Experimental / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D007519:Isoantigens; D017382:Reactive Oxygen Species