Macrocyclic Peptide-Mediated Blockade of the CD47-SIRPα Interaction as a Potential Cancer Immunotherapy.
Allosteric Regulation
Animals
Antigens, CD20
/ immunology
Antineoplastic Agents, Immunological
/ immunology
CD47 Antigen
/ chemistry
Cell Line, Tumor
Female
Humans
Immunotherapy
Macrophages
/ cytology
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Neoplasms
/ mortality
Peptides, Cyclic
/ chemistry
Phagocytosis
Protein Binding
Receptors, Immunologic
/ chemistry
Rituximab
/ immunology
Survival Rate
CD47
SIRPα
cancer
immunotherapy
innate immune checkpoint
macrocyclic peptide
macrophage
phagocytosis
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
17 09 2020
17 09 2020
Historique:
received:
09
04
2020
revised:
30
05
2020
accepted:
12
06
2020
pubmed:
9
7
2020
medline:
2
7
2021
entrez:
9
7
2020
Statut:
ppublish
Résumé
Medium-sized macrocyclic peptides are an alternative to small compounds and large biomolecules as a class of pharmaceutics. The CD47-SIRPα signaling axis functions as an innate immune checkpoint that inhibits phagocytosis in phagocytes and has been implicated as a promising target for cancer immunotherapy. The potential of macrocyclic peptides that target this signaling axis as immunotherapeutic agents has remained unknown, however. Here we have developed a macrocyclic peptide consisting of 15 amino acids that binds to the ectodomain of mouse SIRPα and efficiently blocks its interaction with CD47 in an allosteric manner. The peptide markedly promoted the phagocytosis of antibody-opsonized tumor cells by macrophages in vitro as well as enhanced the inhibitory effect of anti-CD20 or anti-gp75 antibodies on tumor formation or metastasis in vivo. Our results suggest that allosteric inhibition of the CD47-SIRPα interaction by macrocyclic peptides is a potential approach to cancer immunotherapy.
Identifiants
pubmed: 32640189
pii: S2451-9456(20)30231-2
doi: 10.1016/j.chembiol.2020.06.008
pii:
doi:
Substances chimiques
Antigens, CD20
0
Antineoplastic Agents, Immunological
0
CD47 Antigen
0
Peptides, Cyclic
0
Ptpns1 protein, mouse
0
Receptors, Immunologic
0
Rituximab
4F4X42SYQ6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1181-1191.e7Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.