Home LiteratureArticle Details
PMID: 21450901 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Myeloid-derived suppressor cells express the death receptor Fas and apoptose in response to T cell-expressed FasL.

Blood ·Vol. 117 ·No. 20 ·2011-05-19 ·Pages 5381-90

Sinha P, Chornoguz O, Clements VK, Artemenko KA, Zubarev RA, Ostrand-Rosenberg S

Abstract

Myeloid-derived suppressor cells (MDSCs) inhibit adaptive and innate immunity and accumulate in the blood of persons with cancer, chronic inflammation, trauma, infection, and stress. Some of the factors inducing their accumulation are known; however, mechanisms regulating their turnover have not been identified. Mass spectrometry showed prominent expression of apoptosis pathway proteins, suggesting that MDSC turnover may be regulated by Fas-FasL-mediated apoptosis. This hypothesis was confirmed by showing that blood MDSCs induced by 3 mouse tumors were Fas(+) and apoptosed in response to Fas agonist in vitro and to activated FasL(+) T cells in vivo. FasL-deficient mice contained significantly more blood MDSCs than FasL(+/+) mice, and after removal of primary tumors MDSCs regressed in STAT6(-/-) and CD1(-/-) mice but not in STAT6(-/-)FasL(-/-) or CD1(-/-)FasL(-/-) mice. Fas(+) macrophages and dendritic cells did not apoptose in response to activated T cells, indicating that Fas-FasL regulation of myeloid cells was restricted to MDSCs. These results identify a new mechanism regulating MDSC levels in vivo and show a retaliatory relationship between T cells and MDSCs in that MDSCs suppress T-cell activation; however, once activated, T cells mediate MDSC apoptosis.

MeSH Terms
Adoptive Transfer Animals Apoptosis Cell Line, Tumor Fas Ligand Protein/deficiency,genetics,metabolism Female Lymphocyte Activation Mammary Neoplasms, Experimental/immunology,metabolism,pathology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Myeloid Cells/cytology,immunology,metabolism T-Lymphocytes/immunology,metabolism fas Receptor/metabolism
Chemicals
Fas Ligand Protein Fas protein, mouse Fasl protein, mouse fas Receptor
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Sinha Pratima
Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, USA.
Chornoguz Olesya
Clements Virginia K
Artemenko Konstantin A
Zubarev Roman A
Ostrand-Rosenberg Suzanne
References (50)
50 references, click to expand
  1. Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses.
    Clin Cancer Res. 2007 Aug 15;13(16):4840-8 PMID: 17699863
  2. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function.
    J Exp Med. 2006 Nov 27;203(12):2691-702 PMID: 17101732
  3. Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines.
    Cancer Res. 1998 Apr 1;58(7):1486-93 PMID: 9537252
  4. Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma.
    J Immunol. 2008 Jul 1;181(1):346-53 PMID: 18566400
  5. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein.
    J Exp Med. 2008 Sep 29;205(10):2235-49 PMID: 18809714
  6. Myeloid-derived suppressor cells as regulators of the immune system.
    Nat Rev Immunol. 2009 Mar;9(3):162-74 PMID: 19197294
  7. Inhibition of tumor growth using salmonella expressing Fas ligand.
    J Natl Cancer Inst. 2008 Aug 6;100(15):1113-6 PMID: 18664657
  8. Modulation of the antitumor immune response by complement.
    Nat Immunol. 2008 Nov;9(11):1225-35 PMID: 18820683
  9. CD11b+/Gr-1+ immature myeloid cells mediate suppression of T cells in mice bearing tumors of IL-1beta-secreting cells.
    J Immunol. 2005 Dec 15;175(12):8200-8 PMID: 16339559
  10. Analysis of the Salmonella typhimurium proteome through environmental response toward infectious conditions.
    Mol Cell Proteomics. 2006 Aug;5(8):1450-61 PMID: 16684765
  11. CD11b+Ly-6C(hi) suppressive monocytes in experimental autoimmune encephalomyelitis.
    J Immunol. 2007 Oct 15;179(8):5228-37 PMID: 17911608
  12. Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells.
    J Immunol. 1998 Nov 15;161(10):5313-20 PMID: 9820504
  13. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo.
    Blood. 1998 Dec 1;92(11):4150-66 PMID: 9834220
  14. Myeloid-derived suppressor cells: linking inflammation and cancer.
    J Immunol. 2009 Apr 15;182(8):4499-506 PMID: 19342621
  15. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies.
    Cancer Res. 2009 Mar 15;69(6):2514-22 PMID: 19276342
  16. Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma.
    J Immunol. 2000 Dec 1;165(11):6015-9 PMID: 11086031
  17. Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma.
    Cancer Res. 2007 Dec 1;67(23):11438-46 PMID: 18056472
  18. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host.
    Cancer Res. 2006 Jan 15;66(2):1123-31 PMID: 16424049
  19. MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis.
    J Exp Med. 2007 Jun 11;204(6):1463-74 PMID: 17548519
  20. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells.
    Cancer Res. 2007 May 1;67(9):4507-13 PMID: 17483367
  21. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression.
    Cancer Res. 2007 Oct 15;67(20):10019-26 PMID: 17942936
  22. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells.
    J Immunol. 2008 Oct 1;181(7):4666-75 PMID: 18802069
  23. Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression.
    J Immunol. 2006 Jan 1;176(1):284-90 PMID: 16365420
  24. CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress.
    J Immunol. 2006 Feb 15;176(4):2085-94 PMID: 16455964
  25. Human squamous cell carcinomas of the head and neck chemoattract immune suppressive CD34(+) progenitor cells.
    Hum Immunol. 2001 Apr;62(4):332-41 PMID: 11295465
  26. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor.
    Immunity. 2010 Jun 25;32(6):790-802 PMID: 20605485
  27. Expansion of immunoregulatory macrophages by granulocyte-macrophage colony-stimulating factor derived from a murine mammary tumor.
    Cancer Res. 1990 Jan 15;50(2):227-34 PMID: 2136804
  28. The Fas death factor.
    Science. 1995 Mar 10;267(5203):1449-56 PMID: 7533326
  29. Apoptosis signaling pathways and lymphocyte homeostasis.
    Cell Res. 2007 Sep;17(9):759-71 PMID: 17576411
  30. TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells.
    Cell Death Differ. 2008 Dec;15(12):1901-9 PMID: 18820644
  31. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity.
    Clin Cancer Res. 2005 Sep 15;11(18):6713-21 PMID: 16166452
  32. Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis.
    Cancer Res. 2005 Dec 15;65(24):11743-51 PMID: 16357187
  33. The biochemistry of apoptosis.
    Nature. 2000 Oct 12;407(6805):770-6 PMID: 11048727
  34. Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host.
    Blood. 2007 May 15;109(10):4336-42 PMID: 17244679
  35. Identification of dominant signaling pathways from proteomics expression data.
    J Proteomics. 2008 Apr 30;71(1):89-96 PMID: 18541477
  36. Age-related increase of tumor susceptibility is associated with myeloid-derived suppressor cell mediated suppression of T cell cytotoxicity in recombinant inbred BXD12 mice.
    Mech Ageing Dev. 2007 Nov-Dec;128(11-12):672-80 PMID: 18036633
  37. TS/A: a new metastasizing cell line from a BALB/c spontaneous mammary adenocarcinoma.
    Clin Exp Metastasis. 1983 Oct-Dec;1(4):373-80 PMID: 6546207
  38. Storage, expression and function of Fas ligand, the key death factor of immune cells.
    Curr Med Chem. 2008;15(17):1684-96 PMID: 18673218
  39. Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease.
    J Immunol. 2005 Jan 15;174(2):636-45 PMID: 15634881
  40. Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells.
    J Immunol. 2009 Jul 15;183(2):937-44 PMID: 19553533
  41. High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells.
    Cancer Res. 2004 Sep 1;64(17):6337-43 PMID: 15342423
  42. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma.
    J Exp Med. 2005 Oct 3;202(7):931-9 PMID: 16186186
  43. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer.
    J Immunol. 2001 Jan 1;166(1):678-89 PMID: 11123353
  44. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response.
    J Immunol. 2007 Jul 15;179(2):977-83 PMID: 17617589
  45. Unopposed production of granulocyte-macrophage colony-stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen-presenting cell maturation.
    J Immunol. 1999 May 15;162(10):5728-37 PMID: 10229805
  46. Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway.
    Gastroenterology. 2008 Sep;135(3):871-81, 881.e1-5 PMID: 18674538
  47. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells.
    Cancer Res. 2008 Jul 1;68(13):5439-49 PMID: 18593947
  48. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination.
    Cancer Res. 2003 Aug 1;63(15):4441-9 PMID: 12907617
  49. Altered immune function during long-term host-tumor interactions can be modulated to retard autochthonous neoplastic growth.
    J Immunol. 2007 Sep 1;179(5):2851-9 PMID: 17709499
  50. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression.
    Semin Cancer Biol. 2006 Feb;16(1):53-65 PMID: 16168663
Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2010-11-321752
Published
2011-05-19
Epub
2011-00-30
Pages
5381-90
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC3109712
Subset
IM
Grants
NCI NIH HHS · R01 CA084232 · United States
NCI NIH HHS · R01 CA115880 · United States
NCI NIH HHS · R01CA115880 · United States
NCI NIH HHS · R01CA84232 · United States
External Links
PubMed source DOI: 10.1182/blood-2010-11-321752 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2