Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours.
Adaptive Immunity
/ drug effects
Animals
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Collagen
/ metabolism
Disease Models, Animal
Epitopes
/ immunology
Female
Immunity, Innate
/ drug effects
Inflammation
/ pathology
Interleukin-12
/ pharmacology
Melanoma
/ drug therapy
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasm Metastasis
Neoplasms
/ drug therapy
Protein Binding
/ drug effects
Protein Domains
Remission Induction
Tumor Burden
/ drug effects
Tumor Microenvironment
/ drug effects
Journal
Nature biomedical engineering
ISSN: 2157-846X
Titre abrégé: Nat Biomed Eng
Pays: England
ID NLM: 101696896
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
09
07
2019
accepted:
12
03
2020
pubmed:
15
4
2020
medline:
22
7
2020
entrez:
15
4
2020
Statut:
ppublish
Résumé
Checkpoint-inhibitor (CPI) immunotherapy has achieved remarkable clinical success, yet its efficacy in 'immunologically cold' tumours has been modest. Interleukin-12 (IL-12) is a powerful cytokine that activates the innate and adaptive arms of the immune system; however, the administration of IL-12 has been associated with immune-related adverse events. Here we show that, after intravenous administration of a collagen-binding domain fused to IL-12 (CBD-IL-12) in mice bearing aggressive mouse tumours, CBD-IL-12 accumulates in the tumour stroma due to exposed collagen in the disordered tumour vasculature. In comparison with the administration of unmodified IL-12, CBD-IL-12 induced sustained intratumoural levels of interferon-γ, substantially reduced its systemic levels as well as organ damage and provided superior anticancer efficacy, eliciting complete regression of CPI-unresponsive breast tumours. Furthermore, CBD-IL-12 potently synergized with CPI to eradicate large established melanomas, induced antigen-specific immunological memory and controlled tumour growth in a genetically engineered mouse model of melanoma. CBD-IL-12 may potentiate CPI immunotherapy for immunologically cold tumours.
Identifiants
pubmed: 32284554
doi: 10.1038/s41551-020-0549-2
pii: 10.1038/s41551-020-0549-2
doi:
Substances chimiques
Epitopes
0
Interleukin-12
187348-17-0
Collagen
9007-34-5
Banques de données
figshare
['10.6084/m9.figshare.11971371']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
531-543Subventions
Organisme : NCI NIH HHS
ID : R01 CA219304
Pays : United States
Commentaires et corrections
Type : CommentIn
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