Durable antitumor responses to CD47 blockade require adaptive immune stimulation

• Main Authors: Sockolosky, Jonathan T. (Author), Ho, Chia Chi M. (Author), Almo, Steven C. (Author), Garcia, K. Christopher (Author), Dougan, Michael (Contributor), Kauke, Monique Jacqueline (Contributor), Ploegh, Hidde (Contributor), Ingram, Jessica R. (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Massachusetts Institute of Technology. Department of Chemical Engineering (Contributor), Whitehead Institute for Biomedical Research (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: National Academy of Sciences (U.S.), 2016-12-02T20:15:13Z.
• Subjects: Article
• Online Access: Get fulltext

Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47-SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts. Here, we show that CD47 blockade alone or in combination with a tumor-specific antibody fails to generate antitumor immunity against syngeneic B16F10 tumors in mice. Durable tumor immunity required programmed death-ligand 1 (PD-L1) blockade in combination with an antitumor antibody, with incorporation of CD47 antagonism substantially improving response rates. Our results highlight an underappreciated contribution of the adaptive immune system to anti-CD47 adjuvant therapy and suggest that targeting both innate and adaptive immune checkpoints can potentiate the vaccinal effect of antitumor antibody therapy.
National Institutes of Health (U.S.) (Grant R01 CA177684)
Virginia and D.K. Ludwig Fund for Cancer Research
Lustgarten Foundation
National Institutes of Health (U.S.) (Massachusetts General Hospital Division of Gastroenterology. Training Grant T32 DK007191)