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CD47 blockade triggers T cell–mediated destruction of immunogenic tumors

Nature Medicine volume 21, pages 1209–1215 (2015)Cite this article

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Abstract

Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Here, using syngeneic immunocompetent mouse tumor models, we reveal that the therapeutic effects of CD47 blockade depend on dendritic cell but not macrophage cross-priming of T cell responses. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell–deficient mice. In addition, the antitumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of antitumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell–mediated elimination of immunogenic tumors.

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Figure 1: Antitumor effects of anti-CD47 depend on T cells.
Figure 2: Therapeutic effect of anti-CD47 requires CD8+ T cells.
Figure 3: Anti-CD47 triggers the cross-priming ability of DCs.
Figure 4: Type I IFNs are induced during anti-CD47 mediated tumor inhibition and required.
Figure 5: STING signaling is required for anti-CD47–mediated tumor inhibition.
Figure 6: Anti-CD47-mediated immune protection is impaired by some post treatment chemotherapeutics.

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Acknowledgements

We thank R. Schreiber (Washington University, St. Louis) for providing us with anti-IFNAR antibody. Ifnar1fl/fl mice were kindly provided by U. Kalinke from the Institute for Experimental Infection Research. Anti-IFN-γ neutralizing mAb (clone R46A2) was provided by Z. Qin (the Institute of Biophysics, CAS). Some anti-CD47 antibody (clone MIAP301) was provided by W. Frazier (Washington University, St. Louis). This research was in part supported by US National Institutes of Health grants CA141975 and C134563 to Y.-X.F., the National 12.5 major project of China (No. 2012ZX10001006002004) to Y.-X.F. and H.P., Chinese Academy of Sciences grant XDA09030303 and 2012CB910203 to Y.-X.F. and a Dean's Award from Washington University to W.A.F.

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Author notes

  1. Xiaojuan Liu and Meng Michelle Xu: These authors contributed equally to this work.

  2. Yang-Xin Fu and Meng Michelle Xu: These authors jointly supervised this work.

Authors and Affiliations

  1. Institute of Biophysics and the University of Chicago Joint Group for Immunotherapy, Chinese Academy of Science Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Xiaojuan Liu, Hairong Xu, Hua Peng & Yang-Xin Fu

  2. University of Chinese Academy of Sciences, Beijing, China

    Xiaojuan Liu

  3. Department of Pathology and Committee on Immunology, University of Chicago, Chicago, Illinois, USA

    Yang Pu, Kyle Cron, Liufu Deng, Yang-Xin Fu & Meng Michelle Xu

  4. Department of Medicine and Committee on Immunology, University of Chicago, Chicago, Illinois, USA

    Justin Kline

  5. Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, Missouri, USA

    William A Frazier

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Contributions

X.L., Y.P., H.X. and M.M.X. performed experiments. L.D., J.K., W.A.F. and H.P. provided reagents. X.L., M.M.X. and Y.-X.F. designed and organized experiments. K.C., J.K. and H.P. edited the manuscript. X.L., M.M.X. and Y.-X.F. wrote the paper. Y.-X.F. guided the work.

Corresponding author

Correspondence to Yang-Xin Fu.

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Competing interests

W.A.F. is founder and a stockholder of Vasculox, Inc.

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Liu, X., Pu, Y., Cron, K. et al. CD47 blockade triggers T cell–mediated destruction of immunogenic tumors. Nat Med 21, 1209–1215 (2015). https://doi.org/10.1038/nm.3931

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