CD73-Mediated Immunosuppression Is Linked to a Specific Fibroblast Population That Paves the Way for New Therapy in Breast Cancer.
CAF subsets
Tregs
anti-CD73 antibody
breast cancer
immunosuppression
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
23 Nov 2021
23 Nov 2021
Historique:
received:
16
10
2021
revised:
14
11
2021
accepted:
19
11
2021
entrez:
10
12
2021
pubmed:
11
12
2021
medline:
11
12
2021
Statut:
epublish
Résumé
Cancer-associated fibroblasts (CAF) are heterogeneous with multiple functions in breast cancer. Recently, we identified a specific CAF subpopulation (referred to as CAF-S1), which promotes immunosuppression and immunotherapy resistance. Here, by studying a large collection of human samples, we highlight the key function of CD73/NT5E in CAF-S1-mediated immunosuppression in breast cancer. We first reveal that CD73 protein level specifically accumulates in CAF-S1 in breast cancer patients. Interestingly, infiltration of regulatory T lymphocytes (Tregs) is significantly correlated with CD73 expression in stroma but not in epithelium, indicating that CD73 contributes to immunosuppression when expressed in CAF-S1 and not in tumor cells. By performing functional assays based on relevant systems using primary CAF-S1 isolated from patients, we demonstrate that CAF-S1 increase the content in both PD-1+ and CTLA-4+ Tregs. Importantly, the use of a blocking anti-CD73 antibody on CAF-S1 reduces CAF-S1-mediated immunosuppression by preventing expression of these immune checkpoints on Tregs. Our data support the potential clinical benefit of using both anti-CD73 and immune-checkpoint inhibitors in breast cancer patients for inhibiting CAF-S1-mediated immunosuppression and enhancing anti-tumor immune response.
Sections du résumé
BACKGROUND
BACKGROUND
Cancer-associated fibroblasts (CAF) are heterogeneous with multiple functions in breast cancer. Recently, we identified a specific CAF subpopulation (referred to as CAF-S1), which promotes immunosuppression and immunotherapy resistance.
METHODS AND RESULTS
RESULTS
Here, by studying a large collection of human samples, we highlight the key function of CD73/NT5E in CAF-S1-mediated immunosuppression in breast cancer. We first reveal that CD73 protein level specifically accumulates in CAF-S1 in breast cancer patients. Interestingly, infiltration of regulatory T lymphocytes (Tregs) is significantly correlated with CD73 expression in stroma but not in epithelium, indicating that CD73 contributes to immunosuppression when expressed in CAF-S1 and not in tumor cells. By performing functional assays based on relevant systems using primary CAF-S1 isolated from patients, we demonstrate that CAF-S1 increase the content in both PD-1+ and CTLA-4+ Tregs. Importantly, the use of a blocking anti-CD73 antibody on CAF-S1 reduces CAF-S1-mediated immunosuppression by preventing expression of these immune checkpoints on Tregs.
CONCLUSIONS
CONCLUSIONS
Our data support the potential clinical benefit of using both anti-CD73 and immune-checkpoint inhibitors in breast cancer patients for inhibiting CAF-S1-mediated immunosuppression and enhancing anti-tumor immune response.
Identifiants
pubmed: 34884993
pii: cancers13235878
doi: 10.3390/cancers13235878
pmc: PMC8657241
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : French National Cancer Institute
ID : INCa-DGOS-9963
Organisme : French National Cancer Institute
ID : INCa-11692
Organisme : French National Cancer Institute
ID : INCa-DGOS-4654
Organisme : Ligue Nationale Contre le Cancer
ID : Labelisation
Organisme : Inserm
ID : PC201317
Organisme : Institute Curie
ID : Incentive and Cooperative Program Tumor Micro-environment
Organisme : Fondation ARC pour la Recherche sur le Cancer
ID : SIGN'it 2019
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