Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 19, Pages E2646-E2654Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1604268113
Keywords
immunotherapy; protein engineering; cancer; macrophage; T cell
Categories
Funding
- NIH [R01 CA177684]
- Ludwig Foundation
- HHMI
- Lustgarten Foundation
- Stanford Molecular and Cellular Immunobiology NIH Training Grant [5T32 AI072905]
- Massachusetts General Hospital Division of Gastroenterology NIH Training Grant [T32 DK007191]
- Ludwig Cancer Research
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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 (SIRP alpha). Interference with the CD47-SIRP alpha 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.
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