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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CD276 (B7-H3) was expressed most prominently on CAFs and TSKs.
“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
FAP-high fibroblasts are correlated with Treg cell-mediated immunosuppression and poor outcome.
“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]
Clinical analysis supports an inverse association between CAFs and CD8+ T cells.
“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]
Breast cancer shows divergent CAF phenotypes, with FAP as the primary discriminating marker.
“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]
CAFs can help define the immunosuppressive environment, through effects on immune cell activation and impeding infiltration of immune cells into tumors.
“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]
Stromal fibroblasts are a major source of TGF-β in the TME.
“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.”
BackgroundYuan, Z., Li, Y., Zhang, S., Wang, X., Dou, H., Yu, X., Zhang, Z., Yang, S., & Xiao, M. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01744-8 · Cited by 977 · see citing works
“It’s worth to further explore the relationship between Treg and CAFs in various cancers.”
BackgroundTGFβ biology in cancer progression and immunotherapy
Derynck, R., Turley, S. J., & Akhurst, R. J. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0403-1 · Cited by 944 · see citing works
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Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy
Liu, T., Han, C., Wang, S., Fang, P., Ma, Z., Xu, L., & Yin, R. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0770-1 · Cited by 860 · see citing works
Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer.
Kieffer, Y., Hocine, H. R., Gentric, G., Pelon, F., Bernard, C., Bourachot, B., Lameiras, S., Albergante, L., Bonneau, C., Guyard, A., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1384 · Cited by 910 · see citing works
“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.”
BackgroundMethodResultInfluentialA Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia
Baryawno, N., Przybylski, D., Kowalczyk, M. S., Kfoury, Y. S., Sévère, N., Gustafsson, K. U., Kokkaliaris, K. D., Mercier, F., Tabaka, M., Hofree, M., et al. (2019) · Cell · doi:10.1016/j.cell.2019.04.040 · Cited by 882 · see citing works
Intratumoral heterogeneity in cancer progression and response to immunotherapy
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A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer
Wagner, J., Rapsomaniki, M., Chevrier, S., Anzeneder, T., Langwieder, C., Dykgers, A., Rees, M., Ramaswamy, A., Muenst, S. E., Soysal, S. D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.03.005 · Cited by 784 · see citing works
Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer
Wu, F., Yang, J., Liu, J., Wang, Y., Mu, J., Zeng, Q., Deng, S., & Zhou, H. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00641-0 · Cited by 773 · see citing works
“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.”
BackgroundMethodInfluentialIn search of definitions: Cancer‐associated fibroblasts and their markers
Nurmik, M., Ullmann, P., Rodriguez, F., Haan, S., & Letellier, E. (2020) · International Journal of Cancer · doi:10.1002/ijc.32193 · Cited by 739 · see citing works
“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…”
BackgroundThe Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses
Labani‐Motlagh, A., Ashja-Mahdavi, M., & Loskog, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00940 · Cited by 750 · see citing works
“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).”
BackgroundInfluentialDeciphering breast cancer: from biology to the clinic
Nolan, E., Lindeman, G. J., & Visvader, J. E. (2023) · Cell · doi:10.1016/j.cell.2023.01.040 · Cited by 761 · see citing works
Advances in bladder cancer biology and therapy
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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).”
BackgroundFibrosis and cancer: A strained relationship
Piersma, B., Hayward, M.-K., & Weaver, V. M. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188356 · Cited by 686 · see citing works
“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…”
Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges
Martin, J. D., Cabral, H., Stylianopoulos, T., & Jain, R. K. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0308-z · Cited by 688 · see citing works
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“differently in breast cancer subtypes (Luminal A, HER2 and Triple negative) [8].”
BackgroundCancer-associated fibroblasts in the single-cell era
Lavie, D., Ben‐Shmuel, A., Erez, N., & Scherz‐Shouval, R. (2022) · Nature Cancer · doi:10.1038/s43018-022-00411-z · Cited by 636 · see citing works
Fibroblasts as immune regulators in infection, inflammation and cancer
Davidson, S., Coles, M. C., Thomas, T. R., Kollias, G. A., Ludewig, B., Turley, S. J., Brenner, M. B., & Buckley, C. D. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00540-z · Cited by 611 · see citing works
The adenosine pathway in immuno-oncology
Allard, B., Allard, D., Buisseret, L., & Stagg, J. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0382-2 · Cited by 601 · see citing works
Cancer-associated fibroblasts in gastrointestinal cancer
Kobayashi, H., Enomoto, A., Woods, S. L., Burt, A. D., Takahashi, M., & Worthley, D. L. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0115-0 · Cited by 596 · see citing works
Cancer-associated fibroblasts: from basic science to anticancer therapy
Yang, D., Liu, J., Qian, H., & Zhuang, Q. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01013-0 · Cited by 572 · see citing works
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Molecular pathogenesis and systemic therapies for hepatocellular carcinoma
Llovet, J. M., Pinyol, R., Kelley, R. K., El-Khoueiry, A., Reeves, H. L., Wang, X. W., Gores, G. J., & Villanueva, A. (2022) · Nature Cancer · doi:10.1038/s43018-022-00357-2 · Cited by 498 · see citing works
Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer
Buechler, M. B., Fu, W., & Turley, S. J. (2021) · Immunity · doi:10.1016/j.immuni.2021.04.021 · Cited by 494 · see citing works
Fibroblasts in cancer: Unity in heterogeneity
Chhabra, Y., & Weeraratna, A. T. (2023) · Cell · doi:10.1016/j.cell.2023.03.016 · Cited by 488 · see citing works
Pal, B., Chen, Y., Vaillant, F., Capaldo, B. D., Joyce, R., Song, X., Bryant, V. L., Penington, J. S., Stefano, L. D., Ribera, N. T., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020107333 · Cited by 476 · see citing works
“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
Liu, T., Zhou, L., Li, D., Andl, T., & Zhang, Y. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00060 · Cited by 446 · see citing works
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“The presence of a specific subset of CAFs in the microenvironment, CAF-S1, was recently shown to suppress the immune system by attracting and promoting the survival, differentiation, and activation of CD4+CD25+ T lymphocytes [49].”
BackgroundStromal cells in the tumor microenvironment: accomplices of tumor progression?
Zhao, Y. F., Shen, M., Wu, L., Yang, H., Yao, Y., Yang, Q., Du, J., Liu, L., Li, Y., & Bai, Y. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06110-6 · Cited by 443 · see citing works
“…subgroups according to gene expression levels in breast cancer, namely CAF-S1, CAF-S2, CAF-S3, and CAF-S4, of which CAF-S1 can promote the immunosuppressive environment through multiple steps and mechanisms, and CAF-S4 can induce cancer cell invasion through the NOTCH signaling pathway [35].”
Stromal cell diversity associated with immune evasion in human triple‐negative breast cancer
Wu, S. Z., Roden, D. L., Wang, C., Holliday, H., Harvey, K., Cazet, A., Murphy, K. J., Pereira, B., Al‐Eryani, G., Bartoniček, N., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2019104063 · Cited by 436 · see citing works
“MCAM (also known as CD146) has shown to be a robust marker to differentiate perivascular cells from fibroblasts in human tissues (Li et al, 2003; Middleton et al, 2005; Covas et al, 2008; Crisan et al, 2008).”
BackgroundZhang, H., Yue, X., Chen, Z., Liu, C., Wu, W., Zhang, N., Liu, Z., Yang, L., Jiang, Q., Cheng, Q., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01860-5 · Cited by 435 · see citing works
“Concomitant analyses of six biomarkers, including FAP, CD29 (integrin-β1), α-SMA, FSP1, PDGFRβ, and caveolin, characterized four CAF subsets (from CAF-S1 to CAF-S4) with distinct properties in ovarian and breast cancers (BC) [94, 98].”
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Activated fibroblasts in cancer: Perspectives and challenges
Caligiuri, G., & Tuveson, D. A. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.02.015 · Cited by 431 · see citing works
Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations
Affo, S., Nair, A., Brundu, F., Ravichandra, A., Bhattacharjee, S., Matsuda, M., Chin, L., Filliol, A., Wen, W., Song, X., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.03.012 · Cited by 416 · see citing works
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“Although examples of using both bulk and single-cell sequencing data to examine cell-cell communication exist (Camp et al., 2017; Choi et al., 2015; Costa et al., 2018; Puram et al., 2017; Skelly et al., 2018; Zhou et al., 2017), techniques for connecting these features to biological outcomes of…”
Chen, I. X., Chauhan, V. P., Posada, J., Ng, M. R., Wu, M. W., Adstamongkonkul, P., Huang, P., Lindeman, N., Langer, R., & Jain, R. K. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1815515116 · Cited by 406 · see citing works
“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 417 · see citing works
“In human breast cancer, the CAF-S1 subtype is associated with an immunosuppressive environment 13 and cancer cell migration, thus likely promoting metastasis 17 .”
InfluentialSingleCellSignalR: inference of intercellular networks from single-cell transcriptomics
Cabello‐Aguilar, S., Alame, M., Kon-Sun-Tack, F., Fau, C., Lacroix, M., & Colinge, J. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa183 · Cited by 390 · see citing works
Deterministic reprogramming of neutrophils within tumors
Ng, M. S. F., Kwok, I., Tan, L., Shi, C., Cerezo‐Wallis, D., Tan, Y., Leong, K. W. K., Calvo, G. F., Yang, K. L., Zhang, Y., et al. (2024) · Science · doi:10.1126/science.adf6493 · Cited by 400 · see citing works
“Even so, tumor neutrophils had an even longer half-life [41.8 hours; 95% confidence interval (CI) = 39.6 to 46.6] and a predicted life span of 135 hours (up to 5.625 days; 95% CI = 126.5 to 142.4) (Fig.”
BackgroundInfluentialPelon, F., Bourachot, B., Kieffer, Y., Magagna, I., Mermet‐Meillon, F., Bonnet, I., Costa, A., Givel, A.-M., Atieh, Y., Barbazán, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14134-w · Cited by 392 · see citing works
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Galbo, P. M., Zang, X., & Zheng, D. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-4226 · Cited by 377 · see citing works
Towards targeting the breast cancer immune microenvironment
Harris, M., Savas, P., Virassamy, B., O’Malley, M. M. R., Kay, J., Mueller, S. N., Mackay, L., Salgado, R., & Loi, S. (2024) · Nature Reviews. Cancer · doi:10.1038/s41568-024-00714-6 · Cited by 376 · see citing works
“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 .”
InfluentialLi, X., Sun, Z., Peng, G., Xiao, Y. Q., Guo, J., Wu, B., Li, X., Zhou, W., Li, J., Li, Z., et al. (2021) · Theranostics · doi:10.7150/thno.60540 · Cited by 366 · see citing works
“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].”
BackgroundInfluentialXiao, Y., Ma, D., Zhao, S., Suo, C., Shi, J., Xue, M., Ruan, M., Wang, H., Zhao, J., Li, Q., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-3524 · Cited by 354 · see citing works
Friedman, G., Levi-Galibov, O., David, E., Bornstein, C., Giladi, A., Dadiani, M., Mayo, A., Halperin, C., Pevsner‐Fischer, M., Lavon, H., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-0082-y · Cited by 344 · see citing works
Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy
Barrett, R. L., & Puré, E. (2020) · eLife · doi:10.7554/elife.57243 · Cited by 351 · see citing works
Cancer associated-fibroblast-derived exosomes in cancer progression
Li, C., Teixeira, A. F., Zhu, H., & ten Dijke, P. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01463-y · Cited by 341 · see citing works
“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 · see citing works
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 328 · see citing works
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 324 · see citing works
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 319 · see citing works
“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 321 · see citing works
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 320 · see citing works
“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 309 · see citing works
“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 · see citing works
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 318 · see citing works
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 304 · see citing works
“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 307 · see citing works
“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 302 · see citing works
Heterogeneity of the tumor immune microenvironment and its clinical relevance
Jia, Q., Wang, A., Yuan, Y.-X., Zhu, B., & Long, H.-X. (2022) · Experimental Hematology & Oncology · doi:10.1186/s40164-022-00277-y · Cited by 236 · see citing works
“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 304 · see citing works
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 296 · see citing works
“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 293 · see citing works
“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 299 · see citing works
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 293 · see citing works
“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 · see citing works
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 · see citing works
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 289 · see citing works
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 · see citing works
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 · see citing works
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 292 · see citing works
“[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 283 · see citing works
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 283 · see citing works
“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 279 · see citing works
Cancer immune evasion, immunoediting and intratumour heterogeneity
Roerden, M., & Spranger, S. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-024-01111-8 · Cited by 285 · see citing works
“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 260 · see citing works
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 258 · see citing works
“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 263 · see citing works
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 262 · see citing works
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 260 · see citing works
“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 265 · see citing works
“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 273 · see citing works
“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 259 · see citing works
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 258 · see citing works
- 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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