CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer
Kipp Weiskopf, … , Irving L. Weissman, Julien Sage
Kipp Weiskopf, … , Irving L. Weissman, Julien Sage
Published June 13, 2016
Citation Information: J Clin Invest. 2016;126(7):2610-2620. https://doi.org/10.1172/JCI81603.
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CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer

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 (SIRPα), 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 SIRPα 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/SIRPα axis as a potential immunotherapeutic strategy for SCLC. This approach could enable personalized immunotherapeutic regimens in patients with SCLC and other cancers.

Authors

Kipp Weiskopf, Nadine S. Jahchan, Peter J. Schnorr, Sandra Cristea, Aaron M. Ring, Roy L. Maute, Anne K. Volkmer, Jens-Peter Volkmer, Jie Liu, Jing Shan Lim, Dian Yang, Garrett Seitz, Thuyen Nguyen, Di Wu, Kevin Jude, Heather Guerston, Amira Barkal, Francesca Trapani, Julie George, John T. Poirier, Eric E. Gardner, Linde A. Miles, Elisa de Stanchina, Shane M. Lofgren, Hannes Vogel, Monte M. Winslow, Caroline Dive, Roman K. Thomas, Charles M. Rudin, Matt van de Rijn, Ravindra Majeti, K. Christopher Garcia, Irving L. Weissman, Julien Sage

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Figure 4

CD47-blocking antibodies are effective in an orthotopic model of SCLC.

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CD47-blocking antibodies are effective in an orthotopic model of SCLC. (...
(A) Representative images of mice injected with SCLC tumor cells showing tumor growth in the thoracic area (left, arrowhead), with some mice developing metastases to the liver (right, arrowhead). (B) Tumor growth monitored postmortem under normal light (top) and under fluorescent light (for GFP expression, bottom). Scale bar: 2 mm. H, heart. (C) Representative bioluminescence images of NCI-H82 tumors on day 46 after engraftment in control mice (PBS) and mice treated with CD47-blocking antibodies. (D) Bioluminescence measurements over time. Points represent values from individual mice; bars represent median. Note dropout of mice in PBS cohort over time due to mortality. n = 8–9 mice per treatment cohort. *P < 0.05; **P < 0.01, Mann-Whitney U test. (E) Survival of mice bearing NCI-H82 tumors treated with the indicated therapies. P < 0.0001 by Mantel-Cox test. (D and E) Arrows indicate start of treatment.