Weiskopf, Kipp, Jahchan, Nadine S., Schnorr, Peter J., Cristea, Sandra, Ring, Aaron M., Maute, Roy L., Volkmer, Anne K., Volkmer, Jens-Peter, Liu, Jie, Lim, Jing Shan, Yang, Dian, Seitz, Garrett, Wu, Di, Jude, Kevin, Guerston, Heather, Barkal, Amira, Trapani, Francesca, George, Julie, Poirier, John T., Gardner, Eric E., Miles, Linde A., de Stanchina, Elisa, Lofgren, Shane M., Vogel, Hannes, Winslow, Monte M., Dive, Caroline ORCID: 0000-0002-1726-8850, Thomas, Roman K., Rudin, Charles M., van de Rijn, Matt, Majeti, Ravindra, Garcia, K. Christopher, Weissman, Irving L. and Sage, Julien (2016). CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J. Clin. Invest., 126 (7). S. 2610 - 2621. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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Abstract

Small-cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with limited treatment options. CD47 is a cell surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRP alpha), which serves as an inhibitory receptor on macrophages. Here, we found that CD47 is highly expressed on the surface of human SCLC cells; therefore, we investigated CD47-blocking immunotherapies as a potential approach for SCLC treatment. Disruption of the interaction of CD47 with SIRPa using anti-CD47 antibodies induced macrophage-mediated phagocytosis of human SCLC patient cells in culture. In a murine model, administration of CD47-blocking antibodies or targeted inactivation of the Cd47 gene markedly inhibited SCLC tumor growth. Furthermore, using comprehensive antibody arrays, we identified several possible therapeutic targets on the surface of SCLC cells. Antibodies to these targets, including CD56/neural cell adhesion molecule (NCAM), promoted phagocytosis in human SCLC cell lines that was enhanced when combined with CD47-blocking therapies. In light of recent clinical trials for CD47-blocking therapies in cancer treatment, these findings identify disruption of the CD47/SIRP alpha axis as a potential immunotherapeutic strategy for SCLC. This approach could enable personalized immunotherapeutic regimens in patients with SCLC and other cancers.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Weiskopf, KippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jahchan, Nadine S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnorr, Peter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cristea, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ring, Aaron M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maute, Roy L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volkmer, Anne K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volkmer, Jens-PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, JieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Jing ShanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, DianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seitz, GarrettUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, DiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jude, KevinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerston, HeatherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barkal, AmiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trapani, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
George, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poirier, John T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gardner, Eric E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miles, Linde A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Stanchina, ElisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lofgren, Shane M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogel, HannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winslow, Monte M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dive, CarolineUNSPECIFIEDorcid.org/0000-0002-1726-8850UNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudin, Charles M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van de Rijn, MattUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Majeti, RavindraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia, K. ChristopherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weissman, Irving L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sage, JulienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-271577
DOI: 10.1172/JCI81603
Journal or Publication Title: J. Clin. Invest.
Volume: 126
Number: 7
Page Range: S. 2610 - 2621
Date: 2016
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 1558-8238
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SURFACE-ANTIGEN; STEM-CELLS; EXPRESSION; POLARIZATION; THERAPY; SIGNAL; CD47; PHAGOCYTOSIS; PLASTICITY; RITUXIMABMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27157

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