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Antigen-Specific Inhibition of CD8+ T Cell Response by Immature Myeloid Cells in Cancer Is Mediated by Reactive Oxygen Species

Sergei Kusmartsev, Yulia Nefedova, Daniel Yoder and Dmitry I. Gabrilovich
J Immunol January 15, 2004, 172 (2) 989-999; DOI: https://doi.org/10.4049/jimmunol.172.2.989
Sergei Kusmartsev
H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612
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Yulia Nefedova
H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612
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Daniel Yoder
H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612
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Dmitry I. Gabrilovich
H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612
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This article has a correction. Please see:

  • Errata - April 01, 2004

Abstract

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-γ 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.

  • Received July 2, 2003.
  • Accepted November 6, 2003.
  • Copyright © 2004 by The American Association of Immunologists
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The Journal of Immunology: 172 (2)
The Journal of Immunology
Vol. 172, Issue 2
15 Jan 2004
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Antigen-Specific Inhibition of CD8+ T Cell Response by Immature Myeloid Cells in Cancer Is Mediated by Reactive Oxygen Species
Sergei Kusmartsev, Yulia Nefedova, Daniel Yoder, Dmitry I. Gabrilovich
The Journal of Immunology January 15, 2004, 172 (2) 989-999; DOI: 10.4049/jimmunol.172.2.989

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Antigen-Specific Inhibition of CD8+ T Cell Response by Immature Myeloid Cells in Cancer Is Mediated by Reactive Oxygen Species
Sergei Kusmartsev, Yulia Nefedova, Daniel Yoder, Dmitry I. Gabrilovich
The Journal of Immunology January 15, 2004, 172 (2) 989-999; DOI: 10.4049/jimmunol.172.2.989
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