Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host.
Tumor growth promotes the expansion of myeloid suppressor cells. An inverse correlation between natural killer (NK) cell activation and myeloid suppressor cell (MSC) expansion in tumor-bearing patients and mice prompted us to investigate the role of MSCs in controlling NK antitumor cytotocixity. After adoptive transfer to naive recipients, CD11b(+)Gr-1(+) MSCs freshly isolated from spleens of tumor-bearing mice but not naive mice were able to inhibit NK cell cytotoxicity. An in vivo imaging analysis indicates that the removal of tumors resulted in a significant increased ability (P < .05) in NK cell cytotoxicity to eliminate injected YAC-1 cells from the lungs. Fluorescence-activated cell sorter (FACS) analysis of the composition of lung leukocytes further indicates that the removal of tumors also leads to the reduction of MSCs accumulated in the lung. These data suggest that MSCs suppress NK cell cytotoxicity. The inhibition of NK cell cytotoxicity is cell-cell contact dependent. Inhibition of perforin but not granzyme B production was responsible for MSC-mediated inhibition of NK cytotoxicity. Western blot analyses further suggests that MSCs suppress IL-2-mediated NK cell cytotoxicity by affecting the activity of Stat5.
Liu
Cunren
C
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Alabama 35294-0007, USA.
Yu
Shaohua
S
Kappes
John
J
Wang
Jianhua
J
Grizzle
William E
WE
Zinn
Kurt R
KR
Zhang
Huang-Ge
HG
D000230:Adenocarcinoma / Q000276:immunology*; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005260:Female; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D015674:Mammary Neoplasms, Animal / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology* / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019707:Receptors, Chemokine; D050799:STAT5 Transcription Factor; D054353:Perforin