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CD47 blockade triggers T cell–mediated destruction of immunogenic tumors

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.

References

  1. Gardai, S.J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–334 (2005).

    CAS  PubMed  Google Scholar 

  2. Chao, M.P. et al. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci. Transl. Med. 2, 63ra94 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Chao, M.P., Majeti, R. & Weissman, I.L. Programmed cell removal: a new obstacle in the road to developing cancer. Nat. Rev. Cancer 12, 58–67 (2012).

    CAS  Google Scholar 

  4. Oldenborg, P.A. et al. Role of CD47 as a marker of self on red blood cells. Science 288, 2051–2054 (2000).

    CAS  PubMed  Google Scholar 

  5. Blazar, B.R. et al. CD47 (integrin-associated protein) engagement of dendritic cell and macrophage counterreceptors is required to prevent the clearance of donor lymphohematopoietic cells. J. Exp. Med. 194, 541–549 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Barclay, A.N. & Van den Berg, T.K. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annu. Rev. Immunol. 32, 25–50 (2014).

    CAS  PubMed  Google Scholar 

  7. Yamao, T. et al. Negative regulation of platelet clearance and of the macrophage phagocytic response by the transmembrane glycoprotein SHPS-1. J. Biol. Chem. 277, 39833–39839 (2002).

    CAS  PubMed  Google Scholar 

  8. Olsson, M., Bruhns, P., Frazier, W.A., Ravetch, J.V. & Oldenborg, P.A. Platelet homeostasis is regulated by platelet expression of CD47 under normal conditions and in passive immune thrombocytopenia. Blood 105, 3577–3582 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsai, R.K. & Discher, D.E. Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J. Cell Biol. 180, 989–1003 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Poels, L.G. et al. Monoclonal antibody against human ovarian tumor-associated antigens. J. Natl. Cancer Inst. 76, 781–791 (1986).

    CAS  PubMed  Google Scholar 

  11. Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138, 286–299 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Rendtlew Danielsen, J.M., Knudsen, L.M., Dahl, I.M., Lodahl, M. & Rasmussen, T. Dysregulation of CD47 and the ligands thrombospondin 1 and 2 in multiple myeloma. Br. J. Haematol. 138, 756–760 (2007).

    PubMed  Google Scholar 

  14. Chan, K.S. et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc. Natl. Acad. Sci. USA 106, 14016–14021 (2009).

    CAS  PubMed  Google Scholar 

  15. Chan, K.S., Volkmer, J.P. & Weissman, I. Cancer stem cells in bladder cancer: a revisited and evolving concept. Curr. Opin. Urol. 20, 393–397 (2010).

    PubMed  PubMed Central  Google Scholar 

  16. Chao, M.P. et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699–713 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Willingham, S.B. et al. The CD47-signal regulatory protein α (SIRPa) interaction is a therapeutic target for human solid tumors. Proc. Natl. Acad. Sci. USA 109, 6662–6667 (2012).

    CAS  PubMed  Google Scholar 

  18. Chao, M.P. et al. Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Cancer Res. 71, 1374–1384 (2011).

    CAS  PubMed  Google Scholar 

  19. Chao, M.P. et al. Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy. Blood 118, 4890–4901 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Soto-Pantoja, D.R. et al. CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. Cancer Res. 74, 6771–6783 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee, Y. et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114, 589–595 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Brown, E.J. & Frazier, W.A. Integrin-associated protein (CD47) and its ligands. Trends Cell Biol. 11, 130–135 (2001).

    CAS  PubMed  Google Scholar 

  23. Weiskopf, K. et al. Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341, 88–91 (2013).

    CAS  PubMed  Google Scholar 

  24. Tseng, D. et al. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc. Natl. Acad. Sci. USA 110, 11103–11108 (2013).

    CAS  PubMed  Google Scholar 

  25. Burnette, B.C. et al. The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res. 71, 2488–2496 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Diamond, M.S. et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 208, 1989–2003 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Fuertes, M.B. et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. J. Exp. Med. 208, 2005–2016 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Stagg, J. et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc. Natl. Acad. Sci. USA 108, 7142–7147 (2011).

    CAS  PubMed  Google Scholar 

  29. Yang, X. et al. Targeting the tumor microenvironment with interferon-β bridges innate and adaptive immune responses. Cancer Cell 25, 37–48 (2014).

    PubMed  PubMed Central  Google Scholar 

  30. Chen, G.Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826–837 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Desmet, C.J. & Ishii, K.J. Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. Nat. Rev. Immunol. 12, 479–491 (2012).

    CAS  PubMed  Google Scholar 

  32. Kono, H. & Rock, K.L. How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8, 279–289 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. O'Neill, L.A., Golenbock, D. & Bowie, A.G. The history of Toll-like receptors—redefining innate immunity. Nat. Rev. Immunol. 13, 453–460 (2013).

    CAS  PubMed  Google Scholar 

  34. Ishikawa, H. & Barber, G.N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ishikawa, H., Ma, Z. & Barber, G.N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Li, X.D. et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341, 1390–1394 (2013).

    CAS  PubMed  Google Scholar 

  37. Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z.J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

    CAS  PubMed  Google Scholar 

  38. Wu, J. et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826–830 (2013).

    CAS  PubMed  Google Scholar 

  39. Woo, S.R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Obeid, M. et al. Ecto-calreticulin in immunogenic chemotherapy. Immunol. Rev. 220, 22–34 (2007).

    CAS  PubMed  Google Scholar 

  42. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

    CAS  PubMed  Google Scholar 

  43. Takenaka, K. et al. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat. Immunol. 8, 1313–1323 (2007).

    CAS  PubMed  Google Scholar 

  44. Yamauchi, T. et al. Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment. Blood 121, 1316–1325 (2013).

    CAS  PubMed  Google Scholar 

  45. Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    PubMed  PubMed Central  Google Scholar 

  47. Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).

    CAS  PubMed  Google Scholar 

  48. Ma, Y. et al. CCL2/CCR2-dependent recruitment of functional antigen-presenting cells into tumors upon chemotherapy. Cancer Res. 74, 436–445 (2014).

    CAS  PubMed  Google Scholar 

  49. Rovero, S. et al. DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J. Immunol. 165, 5133–5142 (2000).

    CAS  PubMed  Google Scholar 

  50. Oldenborg, P.A., Gresham, H.D. & Lindberg, F.P. CD47-signal regulatory protein α (SIRPα) regulates Fcγ and complement receptor-mediated phagocytosis. J. Exp. Med. 193, 855–862 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

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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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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.

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Correspondence to Yang-Xin Fu.

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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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