Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 7, Pages 2610-2620Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI81603
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Funding
- National Cancer Institute [F30 CA168059, P01 CA139490, P30 CA008748]
- Geoffrey Beene Cancer Research Center
- Stanford Medical Scientist Training Program [NIH-GM07365]
- Stanford University SPARK Program
- California TRDRP post-doctoral fellowship
- Deutsche Forschungsgemeinschaft [VO 1976/1, TH1386/3-1]
- German Cancer Aid (Deutsche Krebshilfe) as part of the SCLC genome sequencing consortium [109679]
- German Ministry of Science and Education (BMBF) [01ZX1303A]
- Howard Hughes Medical Institute
- Joseph & Laurie Lacob Gynecologic/Ovarian Cancer Fund
- Virginia and D.K. Ludwig Fund for Cancer Research
- Lucile Packard Foundation for Children's Health
- LUNGevity Foundation
- Siebel Stem Cell Institute
- Thomas and Stacey Siebel Foundation
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- Department of Energy Office of Biological and Environmental Research
- NIH, National Institute of General Medical Sciences [P41GM103393]
- Cancer Research UK [20465, 19278] Funding Source: researchfish
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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.
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