Modulation of intratumoural myeloid cells, the hallmark of the anti-tumour efficacy induced by a triple combination: tumour-associated peptide, TLR-3 ligand and α-PD-1.
Animals
Antibodies, Monoclonal
/ pharmacology
Cell Proliferation
Drug Combinations
Female
Humans
Ligands
Lymphocytes, Tumor-Infiltrating
/ immunology
Mice
Mice, Inbred C57BL
Myeloid Cells
/ drug effects
Neoplasms
/ drug therapy
Peptide Fragments
/ pharmacology
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
Toll-Like Receptor 3
/ metabolism
Tumor Cells, Cultured
Tumor Microenvironment
/ immunology
Xenograft Model Antitumor Assays
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
20
05
2020
accepted:
10
12
2020
revised:
05
11
2020
pubmed:
4
2
2021
medline:
28
9
2021
entrez:
3
2
2021
Statut:
ppublish
Résumé
Anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibodies (mAbs) show remarkable clinical anti-tumour efficacy. However, rational combinations are needed to extend the clinical benefit to primary resistant tumours. The design of such combinations requires the identification of the kinetics of critical immune cell populations in the tumour microenvironment. In this study, we compared the kinetics of immune cells in the tumour microenvironment upon treatment with immunotherapy combinations with different anti-tumour efficacies in the non-inflamed tumour model TC-1/A9. Tumour-bearing C57BL/6J mice were treated with all possible combinations of a human papillomavirus (HPV) E7 long peptide, polyinosinic-polycytidylic acid (PIC) and anti-PD-1 mAb. Tumour growth and kinetics of the relevant immune cell populations were assessed over time. The involvement of key immune cells was confirmed by depletion with mAbs and immunophenotyping with multiparametric flow cytometry. The maximum anti-tumour efficacy was achieved after intratumoural administration of HPV E7 long peptide and PIC combined with the systemic administration of anti-PD-1 mAb. The intratumoural immune cell kinetics of this combination was characterised by a biphasic immune response. An initial upsurge of proinflammatory myeloid cells led to a further rise in effector CD8 The anti-tumour efficacy of a successful immunotherapy combination in a non-inflamed tumour model relies on an early inflammatory process that remodels the myeloid cell compartment.
Sections du résumé
BACKGROUND
Anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibodies (mAbs) show remarkable clinical anti-tumour efficacy. However, rational combinations are needed to extend the clinical benefit to primary resistant tumours. The design of such combinations requires the identification of the kinetics of critical immune cell populations in the tumour microenvironment.
METHODS
In this study, we compared the kinetics of immune cells in the tumour microenvironment upon treatment with immunotherapy combinations with different anti-tumour efficacies in the non-inflamed tumour model TC-1/A9. Tumour-bearing C57BL/6J mice were treated with all possible combinations of a human papillomavirus (HPV) E7 long peptide, polyinosinic-polycytidylic acid (PIC) and anti-PD-1 mAb. Tumour growth and kinetics of the relevant immune cell populations were assessed over time. The involvement of key immune cells was confirmed by depletion with mAbs and immunophenotyping with multiparametric flow cytometry.
RESULTS
The maximum anti-tumour efficacy was achieved after intratumoural administration of HPV E7 long peptide and PIC combined with the systemic administration of anti-PD-1 mAb. The intratumoural immune cell kinetics of this combination was characterised by a biphasic immune response. An initial upsurge of proinflammatory myeloid cells led to a further rise in effector CD8
CONCLUSIONS
The anti-tumour efficacy of a successful immunotherapy combination in a non-inflamed tumour model relies on an early inflammatory process that remodels the myeloid cell compartment.
Identifiants
pubmed: 33531689
doi: 10.1038/s41416-020-01239-z
pii: 10.1038/s41416-020-01239-z
pmc: PMC8007692
doi:
Substances chimiques
Antibodies, Monoclonal
0
Drug Combinations
0
Ligands
0
PDCD1 protein, human
0
Peptide Fragments
0
Programmed Cell Death 1 Receptor
0
Toll-Like Receptor 3
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1275-1285Références
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