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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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“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.”
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“Immunosuppressive environment Correlates with Specific CAF-S1 Clusters As we showed that CAF-S1 fibroblasts exert immunosuppression in breast and ovarian cancers (8, 10), we next investigated whether this function could be exerted by all CAF-S1 clusters or restricted to specific ones (Fig.”
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“Recently, single-cell RNA-sequencing and conventional RNA-sequencing of human tissues have allowed better unbiased assessment of heterogeneous CAFs.(20,58,59) By analyzing a combination of classical markers, such as FAP and PDGFRβ, CAFs in breast cancer were distinguished by levels of marker expression.”
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Nurmik, M., Ullmann, P., Rodriguez, F., Haan, S., & Letellier, E. (2020) · International Journal of Cancer · doi:10.1002/ijc.32193 · Cited by 739
“A number of studies have already been conducted in order to identify the various CAF subtypes that reside within the overall tumor microenvironment.(23,33,56,89,90,96) These subtypes have been shown to possess extreme variability in regards to their marker expression, with certain subtypes showing almost no expression…”
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“In the TME, MDSCs are activated by various molecular factors such as VEGF, GM-CSF, C5a, MMP9, IFN-γ, TGF-β, IL-1β, IL-6, IL-10, IL-12, IL-13, CCL2, CXCL5, CXCL12, gangliosides, and prostaglandins (111).”
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“Moreover, CAF-S1 were able to increase T cell survival, induce their differentiation to CD4CD25FOXP3 regulatory lymphocytes and to enhance the capacity of Treg cells to inhibit the proliferation of CD4CD25 T cells in vitro (20).”
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“For example, CAFs with low expression of β1 integrin, αSMA, FAP, and PDGFRβ associate primarily with luminal subtypes (less aggressive), whereas CAFs positive for these CAF-associated markers were predominantly found in human epidermal growth factor receptor 2 (HER2) and triple negative breast cancers (TNBC) (more agg…”
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“There is mounting evidence that CAFs are an integral part of the breast tumor microenvironment, playing roles in immunosuppression and mediating response to therapy (Brechbuhl et al, 2017; Cazet et al, 2018; Costa et al, 2018).”
Cancer-Associated Fibroblasts Build and Secure the Tumor Microenvironment
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“As the CXCL12/CXCR4 axis is a known driver of CAFs in breast cancer (32) and CAFs appear central to T-lymphocyte exclusion in bladder and colorectal cancers (7, 33), we next investigated the effects of αSMA cell-specific”
BackgroundInfluentialCancer-associated fibroblast classification in single-cell and spatial proteomics data
Cords, L., Tietscher, S., Anzeneder, T., Langwieder, C., Rees, M., de Souza, N., & Bodenmiller, B. (2023) · Nature Communications · doi:10.1038/s41467-023-39762-1 · Cited by 445
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“CAF-S4 rich tumours have more CD8 + T cells and fewer T reg cells whereas CAF-S1 density correlates with increased CD45 + cells and TAMs but fewer T cells 18 .”
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“We mainly focused on the diversity of CAFs, which regulate different aspects of the biology of the TME. iCAFs chemoattract and regulate the function of T cells by secreting IL6 and CXCL12, which are similar to the inflammatory CAFs identified in other solid tumors [34, 35].”
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Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy
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Cancer associated-fibroblast-derived exosomes in cancer progression
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“Similarly, the presence of CAFs with immunomodulatory function has also been demonstrated in breast cancers [43].”
BackgroundMeflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis
Mizutani, Y., Kobayashi, H., Iida, T., Asai, N., Masamune, A., Hara, A., Esaki, N., Ushida, K., Mii, S., Shiraki, Y., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0454 · Cited by 339
Microenvironmental Determinants of Pancreatic Cancer
Heßmann, E., Buchholz, S., Demir, İ. E., Singh, S. K., Gress, T. M., Ellenrieder, V., & Neeße, A. (2020) · Physiological Reviews · doi:10.1152/physrev.00042.2019 · Cited by 336
Bu, L., Baba, H., Yoshida, N., Miyake, K., Yasuda, T., Uchihara, T., Tan, P. B. O., & Ishimoto, T. (2019) · Oncogene · doi:10.1038/s41388-019-0765-y · Cited by 336
Single-Cell RNA Sequencing Reveals a Dynamic Stromal Niche That Supports Tumor Growth
Davidson, S., Efremova, M., Riedel, A., Mahata, B., Pramanik, J., Huuhtanen, J., Kar, G., Vento‐Tormo, R., Hagai, T., Chen, X. X., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107628 · Cited by 330
“cell technologies have yielded insights into the diversity of the TME, and are beginning to reveal the extent of heterogeneity within the stromal compartment (Bartoschek et al., 2018; Costa et al., 2018; Elyada et al., 2019; Lambrechts et al., 2018; Öhlund et al., 2017; Puram et al., 2017).”
BackgroundResultInfluentialYoshida, G. J. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01611-0 · Cited by 328
Targeting the tumor stroma for cancer therapy
Xu, M., Zhang, T., Xia, R., Wei, Y., & Wei, X. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01670-1 · Cited by 334
“Among them, both CAF-S1 and CAF-S4 subpopulations could be preferentially detected in tumor tissues and were proven to be closely related to tumor cell invasion in a complementary manner [146, 147].”
BackgroundCAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer
Pereira, B., Vennin, C., Papanicolaou, M., Chambers, C. R., Herrmann, D., Morton, J. P., Cox, T. R., & Timpson, P. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.09.010 · Cited by 320
“Furthermore, this functional diversity in CAFs and other stromal populations is mirrored in other malignancies, such as breast [27], lung”
BackgroundAcquired resistance to cancer immunotherapy: Role of tumor-mediated immunosuppression
Saleh, R., & Elkord, E. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.07.017 · Cited by 292
Cords, L., Engler, S., Haberecker, M., Rüschoff, J. H., Moch, H., de Souza, N., & Bodenmiller, B. (2024) · Cancer Cell · doi:10.1016/j.ccell.2023.12.021 · Cited by 334
Imaging mass cytometry and multiplatform genomics define the phenogenomic landscape of breast cancer
Ali, H. R., Jackson, H. W., Zanotelli, V. R., Danenberg, E., Fischer, J. R., Bardwell, H. A., Provenzano, E., CRUK IMAXT Grand Challenge Team, Ali, H. R., Sa’d, M. A., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-0026-6 · Cited by 313
“3 2 Vascular SMA (6) Myofibroblasts (38) Myofibroblasts (42) Myofibroblasts (56) Fibroblasts (1) Myofibroblasts (44) Fibroblasts (21) Myofibroblasts (34) Fibroblasts (4) Myofibroblasts (15) Myofibroblasts (43) Myofibroblasts (17) Fibroblasts (35) HRCK7 (48) Myofibroblasts (39) Fibroblasts (40) Myofibroblasts (11) Fibr…”
BackgroundKoyama, S., & Nishikawa, H. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002591 · Cited by 313
“Because Fc γ RIIB can be induced in activated CD8 + T cells in the TME, FGL2 secreted by Tregs binds to Fc γ RIIB in CD8 + T cells and leads to their apoptosis through caspase 3 and 7 induction.”
BackgroundBiomarkers for cancer-associated fibroblasts
Han, C., Liu, T., & Yin, R. H. (2020) · Biomarker Research · doi:10.1186/s40364-020-00245-w · Cited by 308
Heterogeneity of the tumor immune microenvironment and its clinical relevance
Jia, Q., Wang, A., Yuan, Y., Zhu, B., & Long, H. (2022) · Experimental Hematology and Oncology · doi:10.1186/s40164-022-00277-y · Cited by 332
“Various types of immune cell types show heterogeneous infiltration within tumors, including cytotoxic T lymphocytes (CTLs) [9, 18, 19], myeloid antigen-presentation cells [20], and cancer-associated fibroblasts (CAFs) [21].”
BackgroundGao, Y., Li, J., Cheng, W., Diao, T., Liu, H., Bo, Y., Liu, C., Zhou, W., Chen, M., Zhang, Y., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.08.020 · Cited by 320
Neuzillet, C., Tijeras‐Raballand, A., Ragulan, C., Cros, J. F., Patil, Y., Martinet, M., Erkan, M., Kleeff, J. H., Wilson, J. S., Apte, M. V., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5224 · Cited by 310
“In breast cancer, CAF subtypes have already been proposed as predictive markers of response to immune therapy [52].”
BackgroundBecker, L. M., O’Connell, J. T., Vo, A. P., Cain, M. P., Tampe, D., Bizarro, L., Sugimoto, H., McGow, A. K., Asara, J. M., Lovisa, S., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107701 · Cited by 296
“Breast CAFs are a diverse population of mesenchymal cells identified by various protein markers (Costa et al., 2018; Kalluri, 2016b; Sugimoto et al., 2006; Tchou et al., 2012).”
BackgroundTimperi, E., Gueguen, P., Molgora, M., Magagna, I., Kieffer, Y., Lopez‐Lastra, S., Sirven, P., Baudrin, L. G., Baulande, S., Nicolas, A., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-1427 · Cited by 323
Cancer‐associated fibroblasts in breast cancer: Challenges and opportunities
Hu, D., Li, Z., Zheng, B., Lin, X., Pan, Y., Gong, P., Zhuo, W., Hu, Y., Chen, C., Chen, L., et al. (2022) · 癌症：英文版 · doi:10.1002/cac2.12291 · Cited by 310
“In breast cancer, FAP-positive CAFs mediated Treg activation and exerted immunosuppressive activity in a dipeptidyl peptidase (DPP) 4-dependent manner that was related to a poor outcome [47].”
BackgroundCancer-associated fibroblasts in desmoplastic tumors: emerging role of integrins
Zeltz, C., Primac, I., Erusappan, P., Alam, J., Noel, A., & Gullberg, D. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.08.004 · Cited by 290
Geospatial immune variability illuminates differential evolution of lung adenocarcinoma
AbdulJabbar, K., Raza, S. E. A., Rosenthal, R., Jamal‐Hanjani, M., Veeriah, S., Akarca, A. U., Lund, T., Moore, D. A., Salgado, R., Bakir, M. A., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0900-x · Cited by 287
Triple-negative breast cancer therapeutic resistance: Where is the Achilles' heel?
Bai, X., Ni, J., Beretov, J., Graham, P., & Li, Y. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.10.016 · Cited by 300
Cancer-associated fibroblasts: overview, progress, challenges, and directions
Ping, Q., Yan, R., Cheng, X., Wang, W., Zhong, Y., Hou, Z., Shi, Y., Wang, C., & Li, R. (2021) · Cancer Gene Therapy · doi:10.1038/s41417-021-00318-4 · Cited by 284
Predicting cell-to-cell communication networks using NATMI
Hou, R., Denisenko, E., Ong, H. T., Ramilowski, J. A., & Forrest, A. R. R. (2020) · Nature Communications · doi:10.1038/s41467-020-18873-z · Cited by 285
Signaling pathways in cancer‐associated fibroblasts: recent advances and future perspectives
Fang, Z., Meng, Q., Xu, J., Wang, W., Zhang, B., Liu, J., Liang, C., Hua, J., Zhao, Y., Yu, X., et al. (2022) · 癌症：英文版 · doi:10.1002/cac2.12392 · Cited by 304
“[55] grouped CAFs into four subgroups, in which CAF-subset 1 (CAF-S1)overexpressing FAP promoted the immunosuppressive environment through multistep mechanisms.”
BackgroundJenkins, L., Jungwirth, U., Avgustinova, A., Iravani, M., Mills, A., Haider, S. A., Harper, J. A., & Isacke, C. M. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-4141 · Cited by 293
Cancer-Associated Fibroblasts in Inflammation and Antitumor Immunity
Kennel, K. B., Bozlar, M., Valk, A. F. D., & Greten, F. R. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-1031 · Cited by 297
“Moreover, using single-cell RNA sequencing, Costa and colleagues described a CAF subpopulation termed “CAF-S1” found in breast and ovarian cancers which increased Treg infiltration via production of CXCL12 and enhanced Treg differentiation (12, 47).”
Antitumour immunity regulated by aberrant ERBB family signalling
Kumagai, S., Koyama, S., & Nishikawa, H. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-020-00322-0 · Cited by 288
Cancer immune evasion, immunoediting and intratumour heterogeneity
Roerden, M., & Spranger, S. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-024-01111-8 · Cited by 297
“Cancer-associated fibroblasts are induced by TGFβ, which can be produced by cancer cells through various mechanisms 103,120 .”
Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms
Hu, H., Piotrowska, Z., Hare, P. J., Chen, H., Mulvey, H. E., Mayfield, A., Noeen, S., Kattermann, K. E., Greenberg, M., Williams, A. F., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.09.003 · Cited by 269
Fibroblast heterogeneity in tumor micro-environment: Role in immunosuppression and new therapies
Mhaidly, R., & Mechta‐Grigoriou, F. (2020) · Seminars in Immunology · doi:10.1016/j.smim.2020.101417 · Cited by 267
“Indeed, several CAF subpopulations have been identified and have either tumor-promoting [25, 27, 31-36] or tumor-suppressive effects [37, 38].”
InfluentialSebastian, A., Hum, N. R., Martin, K. A., Gilmore, S. F., Peran, I., Byers, S. W., Wheeler, E. K., Coleman, M. A., & Loots, G. G. (2020) · Cancers · doi:10.3390/cancers12051307 · Cited by 268
Immunomodulation by radiotherapy in tumour control and normal tissue toxicity
Cytlak, U., Dyer, D. P., Honeychurch, J., Williams, K. J., Travis, M. A., & Illidge, T. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00568-1 · Cited by 277
Xiang, H., Ramil, C. P., Hai, J., Zhang, C., Wang, H., Watkins, A. A., Afshar, R., Georgiev, P., Sze, M. A., Song, X. S., et al. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-19-0507 · Cited by 267
“One study has reported that FAPþPDGFRbþ CAFs in breast cancer attract CD4þCD25þ T cells by secretion of CXCL12 and promote CD4þ T-cell differentiation into FOXP3 regulatory T cells by expression of B7H3, CD73, and DPP4 (9), whereas other studies have demonstrated that CAFs contribute to immunosuppressive M2-like TAM i…”
BackgroundResultRoles of cancer-associated fibroblasts (CAFs) in anti- PD-1/PD-L1 immunotherapy for solid cancers
Pei, L., Liu, Y., Liu, L., Gao, S., Gao, X., Feng, Y., Sun, Z., Zhang, Y., & Wang, C. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01731-z · Cited by 270
“Additionally, a study on breast cancer [42], indicated that FAP+PDGFRβ+ CAF in tissues not only released CXCL12 to promote the migration of CD4+CD25+ T cells, but also expressed CD73, dipeptidyl peptidase IV (DPP4) and B7H3 to promote the conversion of CD4+ T cells to FOXP3+ Treg cells.”
BackgroundKundu, M., Butti, R., Panda, V. K., Malhotra, D., Das, S., Mitra, T., Kapse, P., Gosavi, S., & Kundu, G. C. (2024) · Molecular Cancer · doi:10.1186/s12943-024-01990-4 · Cited by 284
“Costa et al. have identified four different subsets of CAFs (CAF-S1 to CAF-S4) with distinct properties and levels of activation in TNBC patients’ specimens by simultaneous analysis of six fibroblast markers (FAP, integrin β1, α-SMA, FSP1, PDGFRβ, and CAV1) [121].”
BackgroundCancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy
Glabman, R. A., Choyke, P. L., & Sato, N. (2022) · Cancers · doi:10.3390/cancers14163906 · Cited by 270
Host tissue determinants of tumour immunity
Salmon, H., Remark, R., Gnjatic, S., & Mérad, M. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0125-9 · Cited by 263
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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