Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells.
The mechanism of tumor-associated T cell dysfunction remains an unresolved problem of tumor immunology. Development of T cell defects in tumor-bearing hosts are often associated with increased production of immature myeloid cells. In tumor-bearing mice, these immature myeloid cells are represented by a population of Gr-1(+) cells. In this study we investigated an effect of these cells on T cell function. Gr-1(+) cells were isolated from MethA sarcoma or C3 tumor-bearing mice using cell sorting. These Gr-1(+) cells expressed myeloid cell marker CD11b and MHC class I molecules, but they lacked expression of MHC class II molecules. Tumor-induced Gr-1(+) cells did not affect T cell responses to Con A and to a peptide presented by MHC class II. In sharp contrast, Gr-1(+) cells completely blocked T cell response to a peptide presented by MHC class I in vitro and in vivo. Block of the specific MHC class I molecules on the surface of Gr-1(+) cells completely abrogated the observed effects of these cells. Thus, immature myeloid cells specifically inhibited CD8-mediated Ag-specific T cell response, but not CD4-mediated T cell response. Differentiation of Gr-1(+) cells in the presence of growth factors and all-trans retinoic acid completely eliminated inhibitory potential of these cells. This may suggest a new approach to cancer treatment.
Gabrilovich
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H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612., USA. dgabril@moffitt.usf.edu
Velders
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Sotomayor
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Kast
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D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D007108:Immune Tolerance / Q000276:immunology*; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation / Q000276:immunology; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009368:Neoplasm Transplantation; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D013154:Spleen / Q000166:cytology / Q000276:immunology
D015395:Histocompatibility Antigens Class I; D008748:Methylcholanthrene