Therapeutic depletion of CCR8
Animals
Antineoplastic Agents, Immunological
/ pharmacology
Carcinoma, Lewis Lung
/ genetics
Combined Modality Therapy
Databases, Genetic
Female
Gene Expression Profiling
Humans
Immune Checkpoint Inhibitors
/ pharmacology
Lung Neoplasms
/ drug therapy
Lymphocyte Depletion
Lymphocytes, Tumor-Infiltrating
/ immunology
Melanoma, Experimental
/ genetics
Mice, Inbred C57BL
Mice, Knockout
Molecular Targeted Therapy
Phenotype
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
RNA-Seq
Receptors, CCR8
/ deficiency
Skin Neoplasms
/ genetics
T-Lymphocytes, Regulatory
/ immunology
biomarkers
immunologic
immunotherapy
lymphocytes
receptors
tumor
tumor-infiltrating
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
accepted:
29
12
2020
entrez:
16
2
2021
pubmed:
17
2
2021
medline:
5
1
2022
Statut:
ppublish
Résumé
Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker. We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models. We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy.
Sections du résumé
BACKGROUND
Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker.
METHODS
We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models.
RESULTS
We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of
CONCLUSIONS
Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy.
Identifiants
pubmed: 33589525
pii: jitc-2020-001749
doi: 10.1136/jitc-2020-001749
pmc: PMC7887378
pii:
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
CCR8 protein, human
0
Ccr8 protein, mouse
0
Immune Checkpoint Inhibitors
0
Pdcd1 protein, mouse
0
Programmed Cell Death 1 Receptor
0
Receptors, CCR8
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: HR and EA are employees of Oncurious NV. PM is a consultant to Oncurious NV.
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