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Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer
Open accessAbstract
Carcinoma-associated fibroblasts (CAF) are key players in the tumor microenvironment. Here, we characterize four CAF subsets in breast cancer with distinct properties and levels of activation. Two myofibroblastic subsets (CAF-S1, CAF-S4) accumulate differentially in triple-negative breast cancers (TNBC). CAF-S1 fibroblasts promote an immunosuppressive environment through a multi-step mechanism. By secreting CXCL12, CAF-S1 attracts CD4+CD25+ T lymphocytes and retains them by OX40L, PD-L2, and JAM2. Moreover, CAF-S1 increases T lymphocyte survival and promotes their differentiation into CD25 High FOXP3 High, through B7H3, CD73, and DPP4. Finally, in contrast to CAF-S4, CAF-S1 enhances the regulatory T cell capacity to inhibit T effector proliferation. These data are consistent with FOXP3+ T lymphocyte accumulation in CAF-S1-enriched TNBC and show how a CAF subset contributes to immunosuppression.
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“Interestingly, CD276 (B7-H3), known to augment Tregs and inhibit T cell responses (Costa et al., 2018, Prasad et al., 2004, Suh et al., 2003), was expressed most prominently on CAFs and TSKs.”
From Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020) · cites this paper as Costa et al., 2018
In the citing paper
“FAP-high fibroblasts are correlated with Treg cell-mediated immunosuppression and a poor outcome119”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [119]
In the citing paper
“Clinical analysis further supports an inverse association between CAFs and CD8+ T cells119.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [119]
In the citing paper
“Breast cancer also shows divergent CAF phenotypes, with the primary discriminating marker being FAP.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [119]
In the citing paper
“Additionally, they can help define the immunosuppressive environment, through effects on immune cell activation and impeding infiltration of immune cells into tumors227–231.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [227]
In the citing paper
“Stromal fibroblasts are a major source of TGF-β in the TME40,227.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [227]
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“For example, fibroblast activation protein-α (FAP-α) + CAFs can increase the survival of CD4 + CD25 + T lymphocytes by secreting CXCL12 and further induce these T cells differentiation into CD4 + CD25 + FOXP3 + Tregs and increase their ability to inhibit CD4 + effector T cell proliferation, thereby contributing to a t…”
BackgroundDissection of intercellular communication using the transcriptome-based framework ICELLNET
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“CAFs exist in a variety of states that can be either immunosuppressive or immunosupportive (3).”
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“CAF-S3 ND Inactivated CAF [45] CD29MedFAPNeg FSP1Med-HiαSMANeg-Low PDGFRβMed CAV1Neg-Low [28,29]”
BackgroundInfluentialThe impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer
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“A recent study in breast cancer identified four CAF subsets with distinct functions and levels of activation and defined the CAF-S1 fibroblast subset as a pivotal regulator of tumor immunosuppression [139].”
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“A recent study indicated that a CAFs subpopulation, named CAF-S1, can reduce motility of CD4+ and CD45+ T lymphocytes via CXCL12 secretion contributing to immunosuppression [31, 46, 47].”
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“Functionally, cancer associated fibroblast-derived inflammasome promoted tumor progression and metastasis by modulating the TME in an immunosuppressive manner by regulating the expression of adhesion molecules and stimulating endothelial cells.”
BackgroundInfluentialCancer-Associated Fibroblast (CAF) Heterogeneity and Targeting Therapy of CAFs in Pancreatic Cancer
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“The heterogeneity of CAFs was very recently characterized in breast and ovarian cancers, identifying at least 4 different CAF subpopulations, referred to as CAF-S1–CAF-S4, with distinct properties and levels of activation (Costa et al., 2018; Givel et al., 2018).”
BackgroundInfluential68Ga-FAPI-PET/CT in patients with various gynecological malignancies
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“In patients with breast cancer, the lesions presented a moderate uptake in relation to a rather high expression of FAP [20, 21].”
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BackgroundFibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer
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“Moreover, CAFs in breast cancer contribute to drug resistance, reduce anti-tumor immunity, and are associated with aggressive tumor behavior and disease recurrence [13].”
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“Notably secreted TGFb can accumulate in the stromal matrix, exerting a powerful immunosuppressive effect on newly infiltrating na€ ve immune cells (9, 10), while CAF-produced CXCL12 can block entry of CD8þ cells into the tumor and attract regulatory T cells, inhibiting effector T-cell proliferation (11, 12).”
BackgroundDeciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer
Croizer, H., Mhaidly, R., Kieffer, Y., Gentric, G., Djerroudi, L., Leclère, R., Pelon, F., Robley, C., Bohec, M., Meng, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47068-z · Cited by 183
“Myeloid-derived suppressor cells are the major immunosuppressive cells found in BC, but they are not detected in the comprehensive BC cellular landscape (Fig.”
Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression
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“Figure 1: The statistical information of the cancers (a) and cancer deaths (b) in 2019 [2].”
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“In addition, an accumulating body of evidence shows that a large amount of stroma is associated with poor prognosis in patients with gastric cancer (6–8); thus, the tumor stroma is thought to contain particularmolecules that promote tumor progression and drug resistance (9, 10).”
BackgroundMetabolic reprogramming and immune evasion: the interplay in the tumor microenvironment
Zhang, H., Li, S., Wang, D., Liu, S. M., Xiao, T., Gu, W., Yang, H., Wang, H. Z., Yang, M., & Chen, P. (2024) · Biomarker Research · doi:10.1186/s40364-024-00646-1 · Cited by 178
“In solid tumors, various inhibitory factors, such as IL-6, IL-10, TGF-β, PGE2, and IDO [133], along-side several cell type, including CAFs [134], TAM-M2 [135], and Treg cells [136], create an immunosuppressive TME.”
BackgroundImmune suppression and reversal of the suppressive tumor microenvironment
Shimizu, K., Iyoda, T., Okada, M., Yamasaki, S., & Fujii, S. (2018) · International Immunology · doi:10.1093/intimm/dxy042 · Cited by 162
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“The CAFs-S1 subpopulation enhanced Treg cell differentiation, recruitment, and activation, thereby promoting breast cancer immunosuppression, similar to the CAFs-S1 subpopulation detected in ovarian cancer [29, 30].”
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Petitprez, F., Lévy, S., Sun, C., Meylan, M., Linhard, C., Becht, É., Elarouci, N., Tavel, D., Roumenina, L. T., Ayadi, M., et al. (2020) · Genome Medicine · doi:10.1186/s13073-020-00783-w · Cited by 176
Shaping Up the Tumor Microenvironment With Cellular Fibronectin
Efthymiou, G., Saint, A., Ruff, M., Rekad, Z., Ciais, D., & Obberghen‐Schilling, E. V. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00641 · Cited by 160
“Various combinations of markers including but not limited to αSMA, FAP, FSP1, CAV1, IL6, VIM, ITGB1, PDGFRα/β have been used to identify CAF subtypes in different tumor tissues using flow cytometry (22, 23) and single cell transcriptomics (12, 24).”
MethodJeong, H. Y., Ham, I.-H., Lee, S. H., Ryu, D., Son, S.-Y., Han, S.-U., Kim, T.-M., & Hur, H. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-0792 · Cited by 156
“Of those cell types, the heterogeneity of cancerassociated fibroblasts (CAF) has been previously well described in pancreatic adenocarcinoma (PDAC) and breast and colon cancers (13, 39, 40) as myofibroblastic CAFs, inflammatory CAFs (iCAF), and antigen-presenting CAFs.”
BackgroundMultipotent stromal cells: One name, multiple identities
Soliman, H., Theret, M., Scott, W., Hill, L., Underhill, T. M., Hinz, B., & Rossi, F. M. V. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.09.001 · Cited by 147
Li, Y., Hu, X., Lin, R., Zhou, G., Zhao, L., Zhao, D., Zhang, Y., Li, W., Zhang, Y., Ma, P., et al. (2022) · Theranostics · doi:10.7150/thno.71833 · Cited by 158
“[8] have identified four subsets of carcinoma-associated fibroblasts (CAF) in breast cancer, and one subset of them promotes an immunosuppressive microenvironment by recruiting CD4+CD25+ T cells.”
BackgroundFriend or foe? The elusive role of hepatic stellate cells in liver cancer
Cogliati, B., Yashaswini, C. N., Wang, S., Sia, D., & Friedman, S. L. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00821-z · Cited by 159
“…some commonalities, CAF subtypes differ between metastases and primary tumours 141 and between different cancer subtypes within the same organ 140 , raising the question of how tissue specificity is conferred and underscoring the need for robust and standardized methods for isolation,…”
BackgroundCancer-Associated Fibroblasts and Tumor-Associated Macrophages in Cancer and Cancer Immunotherapy
Raskov, H., Orhan, A., Gaggar, S., & Gögenur, I. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.668731 · Cited by 150
“In human triple-negative breast cancer, a subset of CAF with myofibroblast characteristics (myCAF) (a-SMA/FAP or S1 CAF) was identified as a key player in immunosuppression through the attraction of Tregs and inhibition of effector T cell proliferation (36) and it was hypothesized that targeting the CAF-S1-mediated im…”
BackgroundCAF-induced physical constraints controlling T cell state and localization in solid tumours
Arpinati, L., Carradori, G., & Scherz‐Shouval, R. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00740-4 · Cited by 162
“CAF-mediated CD8 + T cell exclusion is often accompanied by a simultaneous recruitment of immunosuppressive T reg cells and/or induction of T cell exhaustion 36,41,151,160 (Fig.”
Stromal integrin α11 regulates PDGFRβ signaling and promotes breast cancer progression
Primac, I., Maquoi, E., Blacher, S., Heljäsvaara, R., Deun, J. V., Smeland, H. Y., Canale, A., Louis, T., Stuhr, L. E. B., Sounni, N. E., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci125890 · Cited by 155
“Those direct or indirect effects are related, at least, to their capacity to produce growth factors (5), to promote angiogenesis (10), inflammation (11), and immune response (12), to regulate metabolic reprogramming (13), and to contribute to the remodeling and mechanotransduction of the extracellular matrix (ECM) (14…”
BackgroundMethodCancer-Associated Fibroblasts: Understanding Their Heterogeneity
Louault, K., Li, R., & DeClerck, Y. A. (2020) · Cancers · doi:10.3390/cancers12113108 · Cited by 162
“CAF-S1 also have an immunosuppressive activity through the secretion of IL-6, IL-17, IL-10 and CXCL12 that induce the inhibition of CD4+ T lymphocytes, as well as the activation and the proliferation of Treg lymphocytes [68,70].”
BackgroundRoles of CCL2-CCR2 Axis in the Tumor Microenvironment
Kadomoto, S., Izumi, K., & Mizokami, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168530 · Cited by 152
“CAFs make up the main body of the TME, enhance the traits of cancer tissues, and cause the proliferation and infiltration of cancer cells, angiogenesis, and ECM remodeling [64].”
BackgroundLi, C., Guo, H., Zhai, P., Yan, M., Liu, C., Wang, X., Shi, C., Li, J., Tong, T., Zhang, Z., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-1448 · Cited by 156
Cancer-associated fibroblasts: how do they contribute to metastasis?
Kwa, M. Q., Herum, K. M., & Brakebusch, C. (2019) · Clinical & Experimental Metastasis · doi:10.1007/s10585-019-09959-0 · Cited by 150
Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy
Falcone, I., Conciatori, F., Bazzichetto, C., Ferretti, G., Cognetti, F., Ciuffreda, L., & Milella, M. (2020) · Cancers · doi:10.3390/cancers12102870 · Cited by 151
Cd73: An Emerging Checkpoint for Cancer Immunotherapy
Chen, S., Wainwright, D. A., Wu, J. D., Wan, Y., Matei, D. E., Zhang, Y., & Zhang, B. (2019) · Immunotherapy · doi:10.2217/imt-2018-0200 · Cited by 154
“CD73-expressing CAFs are also detected in human triple negative breast cancer [107] and OC [108].”
BackgroundMonteran, L., Ershaid, N., Doron, H., Zait, Y., Scharff, Y., Ben-Yosef, S., Avivi, C., Barshack, I., Sonnenblick, A., & Erez, N. (2022) · Nature Communications · doi:10.1038/s41467-022-33598-x · Cited by 150
Saha, T., & Lukong, K. E. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.856974 · Cited by 148
The emergence of drug resistance to targeted cancer therapies: Clinical evidence
Sarmento‐Ribeiro, A. B., Scorilas, A., Gonçalves, A. C., Efferth, T., & Trougakos, I. P. (2019) · Drug Resistance Updates · doi:10.1016/j.drup.2019.100646 · Cited by 145
Yamamoto, Y., Kasashima, H., Fukui, Y., Tsujio, G., Yashiro, M., & Maeda, K. (2022) · Cancer Science · doi:10.1111/cas.15609 · Cited by 138
Koncina, E., Nurmik, M., Pozdeev, V. I., Gilson, C., Tsenkova, M., Begaj, R., Stang, S., Gaigneaux, A., Weindorfer, C., Rodriguez, F., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39953-w · Cited by 147
“GatingstrategiestoidentifyCD4 + ,CD8 + ,IL − 17 + Tcellsaswellas macrophages are provided in the Supplementary Figs.”
InfluentialSong, J.-Q., Wei, R.-Y., Liu, C.-C., Zhao, Z.-X., Liu, X.-J., Wang, Y.-N., Liu, F.-L., & Liu, X.-W. (2025) · Nature Communications · doi:10.1038/s41467-025-57465-7 · Cited by 151
“However, apCAFs promote the generation of Treg, which could potentially undermine anti-tumor immunity 29,30 .”
Cancer-associated fibroblasts modify lung cancer metabolism involving ROS and TGF-β signaling
Cruz‐Bermúdez, A., Briviesca, R. L., Vicente-Blanco, R. J., García‐Grande, A., Coronado, M. J., Laine-Menéndez, S., Alfaro, C., Sánchez, J. C., Franco, F., Calvo, V., et al. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.10.450 · Cited by 137
Cancer metabolism and tumor microenvironment: fostering each other?
Yuan, Y., Li, H., Wang, P., Chen, L., Guo, D. S., Jiang, H., He, B., Qin, S., Wang, K., Li, N., et al. (2021) · Science China Life Sciences · doi:10.1007/s11427-021-1999-2 · Cited by 140
“…fibroblast activation protein (FAP), PDGF receptor a/b (PDGFR a/b), collagen1, meflin, caveolin (CAV1), and fibroblast-specific protein 1 (FSP1) are often prototypical CAF markers to identify CAFs from tumors, there is no known all-inclusive CAF marker (Costa et al., 2018; Park et al., 1999).”
BackgroundA population-level digital histologic biomarker for enhanced prognosis of invasive breast cancer
Amgad, M., Hodge, J. M., Elsebaie, M. A. T., Bodelon, C., Puvanesarajah, S., Gutman, D. A., Siziopikou, K. P., Goldstein, J. A., Gaudet, M. M., Teras, L. R., et al. (2024) · Nature Medicine · doi:10.1038/s41591-023-02643-7 · Cited by 137
“In combination, our results are most consistent with the mechanistic model put forth in a previous study 80 and extended by other studies whereby myCAFs maintain an immunosuppressive TME by a TGF-β-mediated reduction of CD8 + infiltration and retention of CD4 + T cells 82 .”
Cancer-associated fibroblasts in radiotherapy: challenges and new opportunities
Wang, Z., Tang, Y., Tan, Y., Wei, Q., & Yu, W. (2019) · Cell Communication and Signaling · doi:10.1186/s12964-019-0362-2 · Cited by 142
“Although the tumor-suppressive mechanisms remain less clear than the tumor-promoting mechanisms [5, 10].”
BackgroundFibroblasts in the Tumor Microenvironment
Truffi, M., Sorrentino, L., & Corsi, F. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-37184-5_2 · Cited by 141
Cancer-associated fibroblasts: The chief architect in the tumor microenvironment
Sarkar, M., Nguyen, T., Gundre, E., Ogunlusi, O., El-Sobky, M. H., Giri, B., & Sarkar, T. R. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1089068 · Cited by 150
“Other approaches involve the use of viral vaccines to broaden the cytotoxic range of therapy effects on tumor cells, and CAFs combined (Chen et al., 2015), CAF-directed drug conjugates, inhibition of CTLA-4 and PD-L1 stagnating tumor progression by increasing intratumoral CD8⁺and CD4⁺ T-cells while reducing T regulato…”
BackgroundInfluentialWang, X., Venet, D., Lifrange, F., Larsimont, D., Rediti, M., Stenbeck, L., Dupont, F., Rouas, G., Garcia, A. J., Craciun, L., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54145-w · Cited by 149
Kang, B., Camps, J., Fan, B., Jiang, H., Ibrahim, M. M., Hu, X., Qin, S., Kirchhoff, D., Chiang, D. Y., Wang, S., et al. (2022) · Genome biology · doi:10.1186/s13059-022-02828-2 · Cited by 142
“They also have been associated with stromal cell activation and communication with CAFs through CD73, DPP4, and B7H3 [75].”
BackgroundA Wnt-Induced Phenotypic Switch in Cancer-Associated Fibroblasts Inhibits EMT in Colorectal Cancer
Mosa, M. H., Michels, B. E., Menche, C., Nicolas, A. M., Darvishi, T., Greten, F. R., & Farin, H. F. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0263 · Cited by 136
“CAFs can be recruited from various sources including resident tissue fibroblasts and mesenchymal stem cells (13) and recent studies have identified diverse CAF populations in solid cancers of breast (14), colon (15), lung (16), and pancreas (17, 18).”
BackgroundRecent Advances and Challenges in Cancer Immunotherapy
Peterson, C. M., Denlinger, N., & Yang, Y. (2022) · Cancers · doi:10.3390/cancers14163972 · Cited by 140
Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities
Jiang, X., Jiang, X., Liu, M., Xing, H., Wang, Z., Huang, L., Mellor, A. L., Wang, W., & Wu, S. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.07.017 · Cited by 133
Metadata
- Authors
- Costa, A., Kieffer, Y., Scholer-Dahirel, A., Pelon, F., Bourachot, B., Cardon, M., Sirven, P., Magagna, I., Fuhrmann, L., Bernard, C., Bonneau, C., Kondratova, M., Kuperstein, I., Zinovyev, A., Givel, A.-M., Parrini, M.-C., Soumelis, V., Vincent-Salomon, A., & Mechta-Grigoriou, F.
- Affiliations
- Inserm (FR)
- Institut Curie (FR)
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 33
- Issue
- 3
- Pages
- 463-479.e10
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2786031287
- Cited by
- 1,705
- References
- 74
- Citations by year
- 2026: 165 · 2025: 202 · 2024: 264 · 2023: 255 · 2022: 236 · 2021: 262 · 2020: 173 · 2019: 99 · 2018: 47
- FWCI
- 54.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Fondation de France
- Fondation Pierre-Gilles de Gennes
- Institut National Du Cancer (INCa-DGOS-9963)
- Fondation pour la Recherche Médicale
- SiRIC-Curie program (INCa-DGOS-4654)
- Institut National de la Santé et de la Recherche Médicale
- Institut Curie
- Ligue Nationale Contre le Cancer
- ICGex (ANR-10-EQPX-03)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- cancer-associated fibroblasts, breast cancer, triple-negative breast cancer, tumor microenvironment, immunosuppression, regulatory T cells, CXCL12, OX40L, PD-L2, JAM2, B7-H3, CD73, dipeptidyl peptidase IV, Foxp3, CD4+ T cells, T cell survival, fibroblast heterogeneity
- MeSH terms
- Breast Neoplasms, Cell Differentiation, Fibroblasts, Humans, Immune Tolerance, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating, Cell Proliferation, T-Lymphocytes, Regulatory, Forkhead Transcription Factors, Tumor Microenvironment
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