Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Modulation of the antitumor immune response by complement

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Complement activation is involved in tumor growth.
Figure 2: Involvement of the classical pathway in the activation of complement during tumor growth.
Figure 3: Lack of C5aR signaling decreases tumor growth with efficiency similar to that of paclitaxel treatment.
Figure 4: The antitumor T cell response is enhanced in mice lacking C5aR signaling.
Figure 5: The migration of myeloid-derived cells into tumors is C5aR dependent.
Figure 6: C5a upregulates CD11b expression in PMN-MDSCs.
Figure 7: C5a enhances the suppressive capacity of tumor-associated MDSCs by regulating the production of ROS and RNS.

References

  1. Dunn, G.P., Bruce, A.T., Ikeda, H., Old, L.J. & Schreiber, R.D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    Article  CAS  Google Scholar 

  2. Swann, J.B. & Smyth, M.J. Immune surveillance of tumors. J. Clin. Invest. 117, 1137–1146 (2007).

    Article  CAS  Google Scholar 

  3. Coussens, L.M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    Article  CAS  Google Scholar 

  4. Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).

    Article  CAS  Google Scholar 

  5. Bhardwaj, N. Harnessing the immune system to treat cancer. J. Clin. Invest. 117, 1130–1136 (2007).

    Article  CAS  Google Scholar 

  6. Lin, W.W. & Karin, M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest. 117, 1175–1183 (2007).

    Article  CAS  Google Scholar 

  7. Blank, C. et al. PD-L1/B7H–1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 64, 1140–1145 (2004).

    Article  CAS  Google Scholar 

  8. Dong, H. et al. Tumor-associated B7–H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).

    Article  CAS  Google Scholar 

  9. Sica, A. & Bronte, V. Altered macrophage differentiation and immune dysfunction in tumor development. J. Clin. Invest. 117, 1155–1166 (2007).

    Article  CAS  Google Scholar 

  10. Kusmartsev, S., Nagaraj, S. & Gabrilovich, D.I. Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J. Immunol. 175, 4583–4592 (2005).

    Article  CAS  Google Scholar 

  11. Kusmartsev, S., Nefedova, Y., Yoder, D. & Gabrilovich, D.I. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J. Immunol. 172, 989–999 (2004).

    Article  CAS  Google Scholar 

  12. Marx, J. Cancer immunology. Cancer's bulwark against immune attack: MDS cells. Science 319, 154–156 (2008).

    Article  CAS  Google Scholar 

  13. Markiewski, M.M. & Lambris, J.D. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am. J. Pathol. 171, 715–727 (2007).

    Article  CAS  Google Scholar 

  14. Carroll, M.C. The complement system in regulation of adaptive immunity. Nat. Immunol. 5, 981–986 (2004).

    Article  CAS  Google Scholar 

  15. Sahu, A. et al. Structure, functions, and evolution of the third complement component and viral molecular mimicry. Immunol. Res. 17, 109–121 (1998).

    Article  CAS  Google Scholar 

  16. Guo, R.F. & Ward, P.A. Role of C5a in inflammatory responses. Annu. Rev. Immunol. 23, 821–852 (2005).

    Article  CAS  Google Scholar 

  17. Gorter, A. & Meri, S. Immune evasion of tumor cells using membrane-bound complement regulatory proteins. Immunol. Today 20, 576–582 (1999).

    Article  CAS  Google Scholar 

  18. Niculescu, F., Rus, H.G., Retegan, M. & Vlaicu, R. Persistent complement activation on tumor cells in breast cancer. Am. J. Pathol. 140, 1039–1043 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Donin, N. et al. Complement resistance of human carcinoma cells depends on membrane regulatory proteins, protein kinases and sialic acid. Clin. Exp. Immunol. 131, 254–263 (2003).

    Article  CAS  Google Scholar 

  20. Macor, P. & Tedesco, F. Complement as effector system in cancer immunotherapy. Immunol. Lett. 111, 6–13 (2007).

    Article  CAS  Google Scholar 

  21. Gelderman, K.A., Tomlinson, S., Ross, G.D. & Gorter, A. Complement function in mAb-mediated cancer immunotherapy. Trends Immunol. 25, 158–164 (2004).

    Article  CAS  Google Scholar 

  22. Lin, K.Y. et al. Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res. 56, 21–26 (1996).

    CAS  PubMed  Google Scholar 

  23. Sahu, A. & Lambris, J.D. Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunol. Rev. 180, 35–48 (2001).

    Article  CAS  Google Scholar 

  24. Monk, P.N., Scola, A.M., Madala, P. & Fairlie, D.P. Function, structure and therapeutic potential of complement C5a receptors. Br. J. Pharmacol. 152, 429–448 (2007).

    Article  CAS  Google Scholar 

  25. Finch, A.M. et al. Low-molecular-weight peptidic and cyclic antagonists of the receptor for the complement factor C5a. J. Med. Chem. 42, 1965–1974 (1999).

    Article  CAS  Google Scholar 

  26. Holtz, D.O. et al. Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclinical modeling in ovarian cancer. J. Transl. Med. 6, 2 (2008).

    Article  Google Scholar 

  27. Johswich, K. et al. Ligand specificity of the anaphylatoxin C5L2 receptor and its regulation on myeloid and epithelial cell lines. J. Biol. Chem. 281, 39088–39095 (2006).

    Article  CAS  Google Scholar 

  28. Movahedi, K. et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T-cell suppressive activity. Blood 111, 4233–4244 (2008).

    Article  CAS  Google Scholar 

  29. Mollnes, T.E. et al. 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 100, 1869–1877 (2002).

    CAS  Google Scholar 

  30. Daniel, D.S. et al. 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. 177, 4688–4698 (2006).

    Article  CAS  Google Scholar 

  31. Guo, R.F. et al. Neutrophil C5a receptor and the outcome in a rat model of sepsis. FASEB J. 17, 1889–1891 (2003).

    Article  CAS  Google Scholar 

  32. de Visser, K.E., Korets, L.V. & Coussens, L.M. Early neoplastic progression is complement independent. Neoplasia 6, 768–776 (2004).

    Article  Google Scholar 

  33. Huber-Lang, M. et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat. Med. 12, 682–687 (2006).

    Article  CAS  Google Scholar 

  34. Shankaran, V. et al. IFN-γ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).

    Article  CAS  Google Scholar 

  35. Smyth, M.J. et al. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J. Exp. Med. 192, 755–760 (2000).

    Article  CAS  Google Scholar 

  36. Hawlisch, H. & Kohl, J. Complement and Toll-like receptors: key regulators of adaptive immune responses. Mol. Immunol. 43, 13–21 (2006).

    Article  CAS  Google Scholar 

  37. Suresh, M. et al. Complement component 3 is required for optimal expansion of CD8 T cells during a systemic viral infection. J. Immunol. 170, 788–794 (2003).

    Article  CAS  Google Scholar 

  38. Kim, A.H. et al. Complement C5a receptor is essential for the optimal generation of antiviral CD8+ T cell responses. J. Immunol. 173, 2524–2529 (2004).

    Article  CAS  Google Scholar 

  39. Liu, J. et al. The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo. J. Exp. Med. 201, 567–577 (2005).

    Article  CAS  Google Scholar 

  40. Kohl, J. & Wills-Karp, M. Complement regulates inhalation tolerance at the dendritic cell/T cell interface. Mol. Immunol. 44, 44–56 (2007).

    Article  CAS  Google Scholar 

  41. Kohl, J. et al. A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma. J. Clin. Invest. 116, 783–796 (2006).

    Article  CAS  Google Scholar 

  42. Karp, C.L. et al. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat. Immunol. 1, 221–226 (2000).

    Article  CAS  Google Scholar 

  43. Peng, T. et al. Role of C5 in the development of airway inflammation, airway hyperresponsiveness, and ongoing airway response. J. Clin. Invest. 115, 1590–1600 (2005).

    Article  CAS  Google Scholar 

  44. Gallina, G. et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J. Clin. Invest. 116, 2777–2790 (2006).

    Article  CAS  Google Scholar 

  45. Mastellos, D. & Lambris, J.D. Complement: more than a 'guard' against invading pathogens? Trends Immunol. 23, 485–491 (2002).

    Article  CAS  Google Scholar 

  46. Mantovani, A., Romero, P., Palucka, A.K. & Marincola, F.M. Tumour immunity: effector response to tumour and role of the microenvironment. Lancet 371, 771–783 (2008).

    Article  CAS  Google Scholar 

  47. Kohl, J. Drug evaluation: the C5a receptor antagonist PMX-53. Curr. Opin. Mol. Ther. 8, 529–538 (2006).

    CAS  PubMed  Google Scholar 

  48. Ricklin, D. & Lambris, J.D. Complement-targeted therapeutics. Nat. Biotechnol. 25, 1265–1275 (2007).

    Article  CAS  Google Scholar 

  49. Circolo, A. et al. Genetic disruption of the murine complement C3 promoter region generates deficient mice with extrahepatic expression of C3 mRNA. Immunopharmacology 42, 135–149 (1999).

    Article  CAS  Google Scholar 

  50. Wessels, M.R. et al. 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. USA 92, 11490–11494 (1995).

    Article  CAS  Google Scholar 

  51. Matsumoto, M. et al. Abrogation of the alternative complement pathway by targeted deletion of murine factor B. Proc. Natl. Acad. Sci. USA 94, 8720–8725 (1997).

    Article  CAS  Google Scholar 

  52. Hopken, U.E., Lu, B., Gerard, N.P. & Gerard, C. The C5a chemoattractant receptor mediates mucosal defence to infection. Nature 383, 86–89 (1996).

    Article  CAS  Google Scholar 

  53. Holland, M.C., Morikis, D. & Lambris, J.D. Synthetic small-molecule complement inhibitors. Curr. Opin. Investig. Drugs 5, 1164–1173 (2004).

    CAS  PubMed  Google Scholar 

  54. Mastellos, D. et al. Novel monoclonal antibodies against mouse C3: Description of fine specificity and applications to various immunoassays. Mol. Immunol. 40, 1213–1221 (2004).

    Article  CAS  Google Scholar 

  55. Strey, C.W. et al. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J. Exp. Med. 198, 913–923 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R.A. Wetsel (University of Texas, Houston) for C3 and factor B–deficient mice; D. Ricklin and C. Tsoukas for critical review of the manuscript; D. McClellan for editorial assistance; the Morphology Core of the Penn Center for Molecular Studies in Digestive and Liver Diseases for technical assistance; Hycult Biotechnology for mAb to C3; and P. Magotti (University of Pennsylvania, Philadelphia) for mouse C5a and for characterizing the C5aR antagonist and control peptide. Supported by the US National Institutes of Health (CA112162-03, GM62134 and A1068730 to J.D.L.).

Author information

Authors and Affiliations

Authors

Contributions

M.M.M. designed and did experiments, analyzed data and wrote the manuscript; R.A.D. contributed to in vivo experiments, data analysis and writing the manuscript; F.B. did T cell proliferation assays and PCR analysis and contributed to flow cytometry experiments; S.K.R.-L. and A.K. contributed to in vivo and flow cytometry experiments; C.G. provided C5aR-deficient mice and advice for the project; G.C. provided advice for the project and reviewed the manuscript; and J.D.L. conceived and supervised the project and coordinated the writing of the manuscript.

Corresponding author

Correspondence to John D Lambris.

Ethics declarations

Competing interests

M.M.M. and J.D.L. have a patent application related to the use of complement inhibitors in cancer therapy.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Methods (PDF 284 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Markiewski, M., DeAngelis, R., Benencia, F. et al. Modulation of the antitumor immune response by complement. Nat Immunol 9, 1225–1235 (2008). https://doi.org/10.1038/ni.1655

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1655

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing