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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.

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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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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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