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Modulation of the antitumor immune response by complement

Nature Immunology volume 9, pages 1225–1235 (2008)Cite this article

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.

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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.

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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.).

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  1. Fabian Benencia

    Present address: Present address: Department of Biomedical Sciences, College of Osteopathic Medicine and Biomedical Engineering Program, Russ College of Engineering and Technology, University of Ohio, Athens, Ohio 45701, USA.,

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Medical School of the University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Maciej M Markiewski, Robert A DeAngelis, Salome K Ricklin-Lichtsteiner, Anna Koutoulaki & John D Lambris

  2. Department of Obstetrics and Gynecology, Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Fabian Benencia & George Coukos

  3. Pulmonary Division, Children's Hospital, Boston, 02215, Massachusetts, USA

    Craig Gerard

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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.

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Correspondence to John D Lambris.

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Competing interests

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

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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

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