Home LiteratureArticle Details
PMID: 18820683 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Modulation of the antitumor immune response by complement.

Nature immunology ·Vol. 9 ·No. 11 ·2008-11-00 ·Pages 1225-35

Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A, Gerard C, Coukos G, Lambris JD

Abstract

The involvement of complement-activation products in promoting tumor growth has not yet been recognized. Here we show that the generation of complement C5a in a tumor microenvironment enhanced tumor growth by suppressing the antitumor CD8(+) T cell-mediated response. This suppression was associated with the recruitment of myeloid-derived suppressor cells into tumors and augmentation of their T cell-directed suppressive abilities. Amplification of the suppressive capacity of myeloid-derived suppressor cells by C5a occurred through regulation of the production of reactive oxygen and nitrogen species. Pharmacological blockade of the C5a receptor considerably impaired tumor growth to a degree similar to the effect produced by the anticancer drug paclitaxel. Thus, our study demonstrates a therapeutic function for complement inhibition in the treatment of cancer.

MeSH Terms
Animals Complement Activation Complement C3-C5 Convertases/genetics Complement C5a/antagonists & inhibitors,immunology,pharmacology Down-Regulation Female Immunosuppression Therapy Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Mutant Strains Myeloid Cells/immunology,metabolism Neoplasms/immunology,therapy Reactive Nitrogen Species/metabolism Reactive Oxygen Species/metabolism Receptor, Anaphylatoxin C5a/antagonists & inhibitors,immunology,metabolism Signal Transduction T-Lymphocytes, Cytotoxic/immunology Xenograft Model Antitumor Assays
Chemicals
Reactive Nitrogen Species Reactive Oxygen Species Receptor, Anaphylatoxin C5a Complement C5a Complement C3-C5 Convertases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Markiewski Maciej M
Department of Pathology and Laboratory Medicine, Medical School of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
DeAngelis Robert A
Benencia Fabian
Ricklin-Lichtsteiner Salome K
Koutoulaki Anna
Gerard Craig
Coukos George
Lambris John D
References (57)
57 references, click to expand
  1. Structure, functions, and evolution of the third complement component and viral molecular mimicry.
    Immunol Res. 1998;17(1-2):109-21 PMID: 9479573
  2. Low-molecular-weight peptidic and cyclic antagonists of the receptor for the complement factor C5a.
    J Med Chem. 1999 Jun 3;42(11):1965-74 PMID: 10354404
  3. Genetic disruption of the murine complement C3 promoter region generates deficient mice with extrahepatic expression of C3 mRNA.
    Immunopharmacology. 1999 May;42(1-3):135-49 PMID: 10408374
  4. Synthetic small-molecule complement inhibitors.
    Curr Opin Investig Drugs. 2004 Nov;5(11):1164-73 PMID: 15573867
  5. Early neoplastic progression is complement independent.
    Neoplasia. 2004 Nov-Dec;6(6):768-76 PMID: 15720803
  6. The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo.
    J Exp Med. 2005 Feb 21;201(4):567-77 PMID: 15710649
  7. Role of C5a in inflammatory responses.
    Annu Rev Immunol. 2005;23:821-52 PMID: 15771587
  8. Role of C5 in the development of airway inflammation, airway hyperresponsiveness, and ongoing airway response.
    J Clin Invest. 2005 Jun;115(6):1590-600 PMID: 15902311
  9. Complement and Toll-like receptors: key regulators of adaptive immune responses.
    Mol Immunol. 2006 Jan;43(1-2):13-21 PMID: 16019071
  10. Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells.
    J Immunol. 2005 Oct 1;175(7):4583-92 PMID: 16177103
  11. HSV oncolytic therapy upregulates interferon-inducible chemokines and recruits immune effector cells in ovarian cancer.
    Mol Ther. 2005 Nov;12(5):789-802 PMID: 15925544
  12. A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma.
    J Clin Invest. 2006 Mar;116(3):783-96 PMID: 16511606
  13. Generation of C5a in the absence of C3: a new complement activation pathway.
    Nat Med. 2006 Jun;12(6):682-7 PMID: 16715088
  14. The reduced bactericidal function of complement C5-deficient murine macrophages is associated with defects in the synthesis and delivery of reactive oxygen radicals to mycobacterial phagosomes.
    J Immunol. 2006 Oct 1;177(7):4688-98 PMID: 16982908
  15. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells.
    J Clin Invest. 2006 Oct;116(10):2777-90 PMID: 17016559
  16. Complement regulates inhalation tolerance at the dendritic cell/T cell interface.
    Mol Immunol. 2007 Jan;44(1-3):44-56 PMID: 16889830
  17. Ligand specificity of the anaphylatoxin C5L2 receptor and its regulation on myeloid and epithelial cell lines.
    J Biol Chem. 2006 Dec 22;281(51):39088-95 PMID: 17068344
  18. Drug evaluation: the C5a receptor antagonist PMX-53.
    Curr Opin Mol Ther. 2006 Dec;8(6):529-38 PMID: 17243489
  19. Harnessing the immune system to treat cancer.
    J Clin Invest. 2007 May;117(5):1130-6 PMID: 17476342
  20. Immune surveillance of tumors.
    J Clin Invest. 2007 May;117(5):1137-46 PMID: 17476343
  21. Altered macrophage differentiation and immune dysfunction in tumor development.
    J Clin Invest. 2007 May;117(5):1155-66 PMID: 17476345
  22. A cytokine-mediated link between innate immunity, inflammation, and cancer.
    J Clin Invest. 2007 May;117(5):1175-83 PMID: 17476347
  23. Complement as effector system in cancer immunotherapy.
    Immunol Lett. 2007 Jul 31;111(1):6-13 PMID: 17572509
  24. The role of complement in inflammatory diseases from behind the scenes into the spotlight.
    Am J Pathol. 2007 Sep;171(3):715-27 PMID: 17640961
  25. Function, structure and therapeutic potential of complement C5a receptors.
    Br J Pharmacol. 2007 Oct;152(4):429-48 PMID: 17603557
  26. Complement-targeted therapeutics.
    Nat Biotechnol. 2007 Nov;25(11):1265-75 PMID: 17989689
  27. Cancer immunology. Cancer's bulwark against immune attack: MDS cells.
    Science. 2008 Jan 11;319(5860):154-6 PMID: 18187637
  28. Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclinical modeling in ovarian cancer.
    J Transl Med. 2008;6:2 PMID: 18182107
  29. Tumour immunity: effector response to tumour and role of the microenvironment.
    Lancet. 2008 Mar 1;371(9614):771-83 PMID: 18275997
  30. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity.
    Blood. 2008 Apr 15;111(8):4233-44 PMID: 18272812
  31. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma.
    J Exp Med. 2000 Sep 4;192(5):755-60 PMID: 10974040
  32. Inflammation and cancer: back to Virchow?
    Lancet. 2001 Feb 17;357(9255):539-45 PMID: 11229684
  33. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma.
    Nat Immunol. 2000 Sep;1(3):221-6 PMID: 10973279
  34. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.
    Nature. 2001 Apr 26;410(6832):1107-11 PMID: 11323675
  35. Structure and biology of complement protein C3, a connecting link between innate and acquired immunity.
    Immunol Rev. 2001 Apr;180:35-48 PMID: 11414361
  36. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.
    Nat Med. 2002 Aug;8(8):793-800 PMID: 12091876
  37. Essential role of the C5a receptor in E coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation.
    Blood. 2002 Sep 1;100(5):1869-77 PMID: 12176911
  38. Complement: more than a 'guard' against invading pathogens?
    Trends Immunol. 2002 Oct;23(10):485-91 PMID: 12297420
  39. Cancer immunoediting: from immunosurveillance to tumor escape.
    Nat Immunol. 2002 Nov;3(11):991-8 PMID: 12407406
  40. Inflammation and cancer.
    Nature. 2002 Dec 19-26;420(6917):860-7 PMID: 12490959
  41. Complement component 3 is required for optimal expansion of CD8 T cells during a systemic viral infection.
    J Immunol. 2003 Jan 15;170(2):788-94 PMID: 12517942
  42. Complement resistance of human carcinoma cells depends on membrane regulatory proteins, protein kinases and sialic acid.
    Clin Exp Immunol. 2003 Feb;131(2):254-63 PMID: 12562385
  43. Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors.
    Mol Immunol. 2003 Sep;40(2-4):109-23 PMID: 12914817
  44. The proinflammatory mediators C3a and C5a are essential for liver regeneration.
    J Exp Med. 2003 Sep 15;198(6):913-23 PMID: 12975457
  45. Neutrophil C5a receptor and the outcome in a rat model of sepsis.
    FASEB J. 2003 Oct;17(13):1889-91 PMID: 12897064
  46. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species.
    J Immunol. 2004 Jan 15;172(2):989-99 PMID: 14707072
  47. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells.
    Cancer Res. 2004 Feb 1;64(3):1140-5 PMID: 14871849
  48. Complement function in mAb-mediated cancer immunotherapy.
    Trends Immunol. 2004 Mar;25(3):158-64 PMID: 15036044
  49. Novel monoclonal antibodies against mouse C3 interfering with complement activation: description of fine specificity and applications to various immunoassays.
    Mol Immunol. 2004 Mar;40(16):1213-21 PMID: 15104126
  50. C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury.
    J Immunol. 2004 Jul 15;173(2):747-54 PMID: 15240660
  51. Complement C5a receptor is essential for the optimal generation of antiviral CD8+ T cell responses.
    J Immunol. 2004 Aug 15;173(4):2524-9 PMID: 15294968
  52. Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A.
    Nat Med. 2004 Sep;10(9):950-8 PMID: 15334073
  53. The complement system in regulation of adaptive immunity.
    Nat Immunol. 2004 Oct;5(10):981-6 PMID: 15454921
  54. Studies of group B streptococcal infection in mice deficient in complement component C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity.
    Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11490-4 PMID: 8524789
  55. Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen.
    Cancer Res. 1996 Jan 1;56(1):21-6 PMID: 8548765
  56. The C5a chemoattractant receptor mediates mucosal defence to infection.
    Nature. 1996 Sep 5;383(6595):86-9 PMID: 8779720
  57. Abrogation of the alternative complement pathway by targeted deletion of murine factor B.
    Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8720-5 PMID: 9238044
Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.1655
Published
2008-11-00
Epub
2008-00-28
Pages
1225-35
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC2678913
Subset
IM
Grants
NIGMS NIH HHS · R01 GM062134-06 · United States
NIAID NIH HHS · P01 AI068730-029001 · United States
NIAID NIH HHS · P01 AI068730-01A1 · United States
NCI NIH HHS · R01 CA112162-03 · United States
NIAID NIH HHS · P01 AI068730-01A10003 · United States
PHS HHS · A1068730 · United States
NCI NIH HHS · R01 CA112162-04 · United States
NIGMS NIH HHS · GM62134 · United States
NIGMS NIH HHS · R01 GM062134 · United States
NCI NIH HHS · R01 CA112162 · United States
NIAID NIH HHS · P01 AI068730 · United States
Corrections
CommentIn
PMID: 18936777
External Links
PubMed source DOI: 10.1038/ni.1655 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