Durable antitumor responses to CD47 blockade require adaptive immune stimulation.
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.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;
Jonathan T
JT
Sockolosky
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;
Michael
M
Dougan
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142;
Jessica R
JR
Ingram
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305; Department of Bioengineering, Stanford University School of Engineering, Stanford, CA 94305;
Chia Chi M
CC
Ho
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
Monique J
MJ
Kauke
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;
Steven C
SC
Almo
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142; kcgarcia@stanford.edu ploegh@wi.mit.edu.
Hidde L
HL
Ploegh
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305 kcgarcia@stanford.edu ploegh@wi.mit.edu.
K Christopher
KC
Garcia
D056704:Adaptive Immunity / Q000187:drug effects / Q000276:immunology; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage* / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology; D051928:CD47 Antigen / Q000187:drug effects* / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D005260:Female; D007114:Immunization / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D051928:CD47 Antigen; D019496:Cancer Vaccines
T cell; cancer; immunotherapy; macrophage; protein engineering