CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer.
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.
Kipp
K
Weiskopf
Nadine S
NS
Jahchan
Peter J
PJ
Schnorr
Sandra
S
Cristea
Aaron M
AM
Ring
Roy L
RL
Maute
Anne K
AK
Volkmer
Jens-Peter
JP
Volkmer
Jie
J
Liu
Jing Shan
JS
Lim
Dian
D
Yang
Garrett
G
Seitz
Thuyen
T
Nguyen
Di
D
Wu
Kevin
K
Jude
Heather
H
Guerston
Amira
A
Barkal
Francesca
F
Trapani
Julie
J
George
John T
JT
Poirier
Eric E
EE
Gardner
Linde A
LA
Miles
Elisa
E
de Stanchina
Shane M
SM
Lofgren
Hannes
H
Vogel
Monte M
MM
Winslow
Caroline
C
Dive
Roman K
RK
Thomas
Charles M
CM
Rudin
Matt
M
van de Rijn
Ravindra
R
Majeti
K Christopher
KC
Garcia
Irving L
IL
Weissman
Julien
J
Sage
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D051928:CD47 Antigen / Q000378:metabolism*; D019002:CD56 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D010587:Phagocytosis; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000276:immunology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; C497894:CD47 protein, human; D019002:CD56 Antigen; C497895:Cd47 protein, mouse; D016207:Cytokines; C522918:NCAM1 protein, human; D011971:Receptors, Immunologic; D049452:Green Fluorescent Proteins