CD73-Mediated Immunosuppression Is Linked to a Specific Fibroblast Population That Paves the Way for New Therapy in Breast Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Description of Retrospective and Prospective Cohorts of Breast Cancer Patients
2.2. CD73 Immunohistochemistry (IHC) Staining in BC Samples
2.3. Quantification of CD73 Histological Scores (HScores) in Epithelial and Stromal Compartments of BC Samples
2.4. Establishment of CAF-S1 Primary Cell Lines from BC Samples
2.5. Characterization of CAF-S1 by Flow Cytometry Analysis
2.6. Measurement of CD73 Protein Levels in CAF-S1 by Flow Cytometry
2.7. Measurement of Exogenous AMP Hydrolysis
2.8. Isolation of Peripheral Mononuclear Cells (PBMCs) from Healthy Donors
2.9. Isolation of CD4+ CD25+ T Cells from Healthy Donor PBMCs
2.10. Co-Culture of CAF-S1 with CD4+ CD25+ T Cells after anti-CD73 Antibody Treatment
2.11. Treg Cell Suppressive Assay
2.12. Statistical Analysis
3. Results
3.1. Accumulation of Regulatory T Lymphocytes in Breast Cancer Is Correlated with CD73 Expression in the Stroma
3.2. CAF-S1 Primary Fibroblasts Exhibit High CD73 Enzymatic Activity
3.3. CD73+ CAF-S1 Primary Fibroblasts Promote the Increase in PD-1+ CTLA-4+ FOXP3+ CD4+ CD25+ T Lymphocytes
3.4. Anti-CD73 Antibody Impairs CAF-S1-Mediated Immunosuppression by Preventing PD-1 and CTLA-4 Up-Regulation in Tregs
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Retrospective Cohort | Prospective Cohort | ||||||
---|---|---|---|---|---|---|---|
Total number of patients | 215 | 26 | |||||
Gender | Female | 215 | 25 (96%) | ||||
Male | 0 | 1 (4%) | |||||
Date of Inclusion | 2004–2012 | 2013–2020 | |||||
Mean follow-up (years) | 7.7 | 1.5 | |||||
Mean age at diagnosis (years) | 55 (22 min–87 max) | 53 (29 min–76 max) | |||||
I | 41 (19%) | 3 (11%) | |||||
Histological grade | II III | 67 (31%) 105 (49%) | 9 (35%) 13 (50%) | ||||
NA | 2 (1%) | 1 (4%) | |||||
pT0 | 0 | 3 (11%) | |||||
pT1 | 146 (68%) | 10 (39%) | |||||
Pathological tumor | pT2 | 62 (29%) | 11 (42%) | ||||
size (pT) | pT3 | 4 (1.5%) | 1 (4%) | ||||
pT4 | 3 (1.5%) | 0 | |||||
NA | 0 | 1 (4%) | |||||
Pathological Lymph node status (pN) | Negative Positive NA | 127 (59%) 86 (40%) 2 (1%) | 21 (81%) 4 (15%) 1 (4%) | ||||
Metastatic status | Negative Positive NA | 203 (94%) 3 (2%) 9 (4%) | 25 (96%) 0 1 (4%) | ||||
Mean tumor size (mm) | 19 | 23.7 | |||||
Lum A | 96 (45%) | 9 (35%) | |||||
Breast cancer subtype | Lum B HER2 | - 54 (25%) | 3 (11.5%) 3 (11.5%) | ||||
TN | 65 (30%) | 11 (42%) | |||||
CAF-S1 | 32 (15%) | - | |||||
CAF-S2 | 38 (18%) | - | |||||
CAF enrichment | CAF-S3 | 3 (1%) | - | ||||
CAF-S4 | 111 (52%) | - | |||||
NA | 31 (14%) | - | |||||
CAF-S1 | CAF-S2 | CAF-S3 | CAF-S4 | NA | |||
CAF enrichment in breast cancer subtypes | LumA HER2 | 6 (6%) | 34 (35%) | 1 (1%) | 40 (42%) | 15 (16%) | - - |
9 (17%) | 2 (3%) | 1 (2%) | 33 (61%) | 9 (17%) | |||
TN | 16 | 2 | 1 | 38 | 8 | - | |
(25%) | (3%) | (1%) | (59%) | (12%) | |||
Yes | 85 (39%) | 11 (42%) | |||||
Hormonotherapy | No | 126 (59%) | 0 | ||||
NA | 4 (2%) | 15 (58%) | |||||
Yes | 204 (95%) | 21 (81%) | |||||
Radiotherapy | No | 0 | 4 (15%) | ||||
NA | 11 (5%) | 1 (4%) | |||||
Yes | 141 (66%) | 19 (73%) | |||||
Chemotherapy | No | 0 | 0 | ||||
NA | 74 (34%) | 7 (27%) | |||||
Yes | 45 (21%) | 2 (8%) | |||||
Targeted therapy | No | 0 | 0 | ||||
NA | 170 (79%) | 24 (92%) |
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Magagna, I.; Gourdin, N.; Kieffer, Y.; Licaj, M.; Mhaidly, R.; Andre, P.; Morel, A.; Vincent-Salomon, A.; Paturel, C.; Mechta-Grigoriou, F. CD73-Mediated Immunosuppression Is Linked to a Specific Fibroblast Population That Paves the Way for New Therapy in Breast Cancer. Cancers 2021, 13, 5878. https://doi.org/10.3390/cancers13235878
Magagna I, Gourdin N, Kieffer Y, Licaj M, Mhaidly R, Andre P, Morel A, Vincent-Salomon A, Paturel C, Mechta-Grigoriou F. CD73-Mediated Immunosuppression Is Linked to a Specific Fibroblast Population That Paves the Way for New Therapy in Breast Cancer. Cancers. 2021; 13(23):5878. https://doi.org/10.3390/cancers13235878
Chicago/Turabian StyleMagagna, Ilaria, Nicolas Gourdin, Yann Kieffer, Monika Licaj, Rana Mhaidly, Pascale Andre, Ariane Morel, Anne Vincent-Salomon, Carine Paturel, and Fatima Mechta-Grigoriou. 2021. "CD73-Mediated Immunosuppression Is Linked to a Specific Fibroblast Population That Paves the Way for New Therapy in Breast Cancer" Cancers 13, no. 23: 5878. https://doi.org/10.3390/cancers13235878