Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Fibroblasts as immune regulators in infection, inflammation and cancer

Abstract

In chronic infection, inflammation and cancer, the tissue microenvironment controls how local immune cells behave, with tissue-resident fibroblasts emerging as a key cell type in regulating activation or suppression of an immune response. Fibroblasts are heterogeneous cells, encompassing functionally distinct populations, the phenotypes of which differ according to their tissue of origin and type of inciting disease. Their immunological properties are also diverse, ranging from the maintenance of a potent inflammatory environment in chronic inflammation to promoting immunosuppression in malignancy, and encapsulating and incarcerating infectious agents within tissues. In this Review, we compare the mechanisms by which fibroblasts control local immune responses, as well as the factors regulating their inflammatory and suppressive profiles, in different tissues and pathological settings. This cross-disease perspective highlights the importance of tissue context in determining fibroblast–immune cell interactions, as well as potential therapeutic avenues to exploit this knowledge for the benefit of patients with chronic infection, inflammation and cancer.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Fibroblast heterogeneity in health and disease across tissues.
Fig. 2: Common mechanisms regulating pro-inflammatory and remodelling populations across diseases.
Fig. 3: Transformation of fibroblast functions in inflammation.
Fig. 4: Fibroblast-mediated immune modulation in cancer.
Fig. 5: Harnessing fibroblasts for therapeutics.

Similar content being viewed by others

References

  1. Duvall, M. Atlas d’Embryologie (Masson, France, 1879).

  2. Tarin, D. & Croft, C. Ultrastructural features of wound healing in mouse skin. J. Anat. 105, 189–190 (1969).

    CAS  PubMed  Google Scholar 

  3. Pierer, M. et al. Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. J. Immunol. 172, 1256–1265 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Bombardieri, M. et al. A BAFF/APRIL-dependent TLR3-stimulated pathway enhances the capacity of rheumatoid synovial fibroblasts to induce AID expression and Ig class-switching in B cells. Ann. Rheum. Dis. 70, 1857–1865 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Brentano, F., Schorr, O., Gay, R. E., Gay, S. & Kyburz, D. RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3. Arthritis Rheum. 52, 2656–2665 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Seki, E. & Brenner, D. A. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48, 322–335 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Henderson, N. C., Rieder, F. & Wynn, T. A. Fibrosis: from mechanisms to medicines. Nature 587, 555–566 (2020). A recent review of the mechanisms regulating fibrosis including a comprehensive view of the role of fibroblasts, their heterogeneity and their tissue interactions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Castor, C. W., Prince, R. K. & Dorstewitz, E. L. Characteristics of human “fibroblasts” cultivated in vitro from different anatomical sites. Lab. Invest. 11, 703–713 (1962).

    CAS  PubMed  Google Scholar 

  9. Chang, H. Y. et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc. Natl Acad. Sci. USA 99, 12877–12882 (2002). The first article to uncover positional memory in cultured skin fibroblasts. Fibroblasts isolated from different anatomical locations display transcriptional differences that are maintained across passages and this implicates a role for HOX genes in this process.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rinn, J. L., Bondre, C., Gladstone, H. B., Brown, P. O. & Chang, H. Y. Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genet. 2, e119 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Frank-Bertoncelj, M. et al. Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions. Nat. Commun. 8, 14852 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730.e22 (2019). A large scRNA-seq atlas of ulcerative colitis including inflamed and adjacent non-inflamed intestinal biopsy samples alongside healthy control samples consisting of 366,650 cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Culemann, S. et al. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature 572, 670–675 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Krausgruber, T. et al. Structural cells are key regulators of organ-specific immune responses. Nature 583, 296–302 (2020). A landmark article in which the transcriptome and epigenome of epithelial cells, endothelial cells and fibroblasts residing in different organs were profiled. This revealed imprinted immune programmes unique to the surrounding tissue that are activated upon viral infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Huang, Y. et al. Single cell transcriptomic analysis of human mesenchymal stem cells reveals limited heterogeneity. Cell Death Dis. 10, 1–12 (2019).

    Article  CAS  Google Scholar 

  16. Kinchen, J. et al. Structural remodeling of the human colonic mesenchyme in inflammatory bowel disease. Cell 175, 372–386.e17 (2018). The first study to sequence the intestinal stroma affected by ulcerative colitis at the single-cell level. This revealed unique fibroblast subsets whose transcriptome implicates unique functions. In particular, this article highlights expansion of a potential pathogenic population.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zepp, J. A. et al. Distinct mesenchymal lineages and niches promote epithelial self-renewal and myofibrogenesis in the lung. Cell 170, 1134–1148.e10 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Janson, D. G., Saintigny, G., van Adrichem, A., Mahé, C. & el Ghalbzouri, A. Different gene expression patterns in human papillary and reticular fibroblasts. J. Invest. Dermatol. 132, 2565–2572 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Lee, D. Y. & Cho, K. H. The effects of epidermal keratinocytes and dermal fibroblasts on the formation of cutaneous basement membrane in three-dimensional culture systems. Arch. Dermatol. Res. 296, 296–302 (2005).

    Article  PubMed  Google Scholar 

  20. Sorrell, J. M., Baber, M. A. & Caplan, A. I. Site-matched papillary and reticular human dermal fibroblasts differ in their release of specific growth factors/cytokines and in their interaction with keratinocytes. J. Cell. Physiol. 200, 134–145 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Dobie, R. et al. Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis. Cell Rep. 29, 1832–1847.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Öhlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017). One of the first articles to identify functionally distinct fibroblasts in cancer. Here, IL-6- and αSMA- expressing fibroblast subsets observed in pancreatic cancer could be replicated in an in vitro culture system. Examination of these cultures suggested distinct roles in immune crosstalk and matrix desmoplasia, respectively, leading to the terms ‘iCAFs’ and ‘myCAFs’.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Monteran, L. & Erez, N. The dark side of fibroblasts: cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment. Front. Immunol. 10, 1835 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bartoschek, M. et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat. Commun. 9, 5150 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479.e10 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Davidson, S. et al. Single-cell RNA sequencing reveals a dynamic stromal niche that supports tumor growth. Cell Rep. 31, 107628 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lambrechts, D. et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24, 1277–1289 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Puram, S. V. et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 171, 1611–1624.e24 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Su, S. et al. CD10+GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172, 841–856.e16 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Brechbuhl, H. M. et al. Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clin. Cancer Res. 23, 1710–1721 (2017).

    Article  CAS  PubMed  Google Scholar 

  34. Kieffer, Y. et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 10, 1330–1351 (2020).

    Article  CAS  PubMed  Google Scholar 

  35. Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019). An article showing that pathogenic functions of fibroblasts in RA differ according to their location in the lining layer and the sublining layer. Here, THY1+ sublining-layer fibroblasts promote inflammation, whereas THY1 cells in the lining layer induce cartilage and bone damage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wei, K. et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature 582, 259–264 (2020). An article identifying the importance of local tissue cues to maintain fibroblast subset identity in RA. The endothelium is critical for the maintenance and expansion of the sublining-layer population.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nygaard, G. & Firestein, G. S. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat. Rev. Rheumatol. 16, 316–333 (2020). A recent review of the role of fibroblasts in RA.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhang, F. et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 20, 928–942 (2019). An article demonstrating that the composition of functionally distinct lining-layer and sublining-layer fibroblasts depends on the disease context. Inflammatory sublining-layer fibroblasts are enriched in leukocyte-rich RA, whereas lining-layer fibroblasts are enriched in leukocyte-poor RA and osteoarthritis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Biffi, G. et al. IL1-induced Jak/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 9, 282–301 (2019). A key article highlighting the plasticity between iCAF and myCAF populations. A positive-feedback loop via NF-κB, LIF and the JAK–STAT pathway propagates the iCAF phenotype. However, perturbation of this feedback loop by TGFβ induces a myCAF phenotype.

    Article  PubMed  Google Scholar 

  40. Crowley, T. et al. Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not dermal fibroblasts. Arthritis Res. Ther. 19, 35 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Erez, N., Truitt, M., Olson, P. & Hanahan, D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 17, 135–147 (2010). One of the first articles to identify the key role of NF-κB in regulating production of inflammatory factors by CAFs.

    Article  CAS  PubMed  Google Scholar 

  42. Koliaraki, V., Pasparakis, M. & Kollias, G. IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer. J. Exp. Med. 212, 2235–2251 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sohn, C. et al. Prolonged tumor necrosis factor α primes fibroblast-like synoviocytes in a gene-specific manner by altering chromatin. Arthritis Rheumatol. 67, 86–95 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang, X. et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Cancer Res. 76, 4124–4135 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. Jones, D. S. et al. Profiling drugs for rheumatoid arthritis that inhibit synovial fibroblast activation. Nat. Chem. Biol. 13, 38–45 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Koliaraki, V. et al. Innate sensing through mesenchymal TLR4/MyD88 signals promotes spontaneous intestinal tumorigenesis. Cell Rep. 26, 536–545.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ospelt, C. et al. Overexpression of Toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: Toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum. 58, 3684–3692 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Seki, E. et al. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Zhao, S. et al. Selective deletion of MyD88 signaling in αSMA positive cells ameliorates experimental intestinal fibrosis via post-transcriptional regulation. Mucosal Immunol. 13, 665–678 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Armaka, M. et al. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. J. Exp. Med. 205, 331–337 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nguyen, H. N. et al. Autocrine loop involving IL-6 family member LIF, LIF receptor, and STAT4 drives sustained fibroblast production of inflammatory mediators. Immunity 46, 220–232 (2017). An article identifying a positive-feedback loop involving NF-κB, LIF and the JAK–STAT pathway, which propagates the inflammatory phenotype of synovial fibroblasts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Aschenbrenner, D. et al. Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance. Gut 0, 1–14 (2020).

    Google Scholar 

  53. le Goff, B. et al. Oncostatin M acting via OSMR, augments the actions of IL-1 and TNF in synovial fibroblasts. Cytokine 68, 101–109 (2014).

    Article  PubMed  CAS  Google Scholar 

  54. West, N. R. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease. Nat. Med. 23, 579–589 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Calvo, F. et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat. Cell Biol. 15, 637–646 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Vaughan, M. B., Howard, E. W. & Tomasek, J. J. Transforming growth factor-β1 promotes the morphological and functional differentiation of the myofibroblast. Exp. Cell Res. 257, 180–189 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wohlfahrt, T. et al. PU.1 controls fibroblast polarization and tissue fibrosis. Nature 566, 344–349 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Parsonage, G. et al. A stromal address code defined by fibroblasts. Trends Immunol. 26, 150–156 (2004). A review exploring the importance of stromal adhesion molecules and chemoattractants, termed the ‘stromal address code’, in dictating the identity and phenotype of immune cells in different tissues.

    Article  CAS  Google Scholar 

  60. Junt, T., Scandella, E. & Ludewig, B. Form follows function: lymphoid tissue microarchitecture in antimicrobial immune defence. Nat. Rev. Immunol. 8, 764–775 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Tikhonova, A. N. et al. The bone marrow microenvironment at single-cell resolution. Nature 569, 222–228 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, Bil & Nagasawa, T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20, 707–718 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Krishnamurty, A. T. & Turley, S. J. Lymph node stromal cells: cartographers of the immune system. Nat. Immunol. 21, 369–380 (2020). A comprehensive review of the mechanisms used by FRCs to regulate immune responses in the lymph node.

    Article  CAS  PubMed  Google Scholar 

  64. Cheng, H. W. et al. Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp. Nat. Commun. 10, 1–14 (2019).

    Article  CAS  Google Scholar 

  65. Perez-Shibayama, C. et al. Type I interferon signaling in fibroblastic reticular cells prevents exhaustive activation of antiviral CD8+ T cells. Sci. Immunol. 5, eabb7066 (2020).

    Article  CAS  PubMed  Google Scholar 

  66. Pikor, N. B. et al. Integration of Th17- and lymphotoxin-derived signals initiates meningeal-resident stromal cell remodeling to propagate neuroinflammation. Immunity 43, 1160–1173 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Rodda, L. B. et al. Single-cell RNA sequencing of lymph node stromal cells reveals niche-associated heterogeneity. Immunity 48, 1014–1028.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Luther, S. A. et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J. Immunol. 169, 424–433 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Luther, S. A., Tang, H. L., Hyman, P. L., Farr, A. G. & Cyster, J. G. Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the plt/plt mouse. Proc. Natl Acad. Sci. USA 97, 12694–12699 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bajénoff, M. et al. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25, 989–1001 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Wang, X. et al. Follicular dendritic cells help establish follicle identity and promote B cell retention in germinal centers. J. Exp. Med. 208, 2497–2510 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jarjour, M. et al. Fate mapping reveals origin and dynamics of lymph node follicular dendritic cells. J. Exp. Med. 211, 1109–1122 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wu, Y. et al. IL-6 produced by immune complex-activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation. Int. Immunol. 21, 745–756 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Knoblich, K. et al. The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation. PLoS Biol. 16, e2005046 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Fletcher, A. L. et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J. Exp. Med. 207, 689–697 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lee, J. W. et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat. Immunol. 8, 181–190 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Pikor, N. B. et al. Remodeling of light and dark zone follicular dendritic cells governs germinal center responses. Nat. Immunol. 21, 649–659 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gregory, J. L. et al. Infection programs sustained lymphoid stromal cell responses and shapes lymph node remodeling upon secondary challenge. Cell Rep. 18, 406–418 (2017).

    Article  CAS  PubMed  Google Scholar 

  80. Majumder, S. et al. IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival. Nat. Immunol. 20, 534–545 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tan, K. W. et al. Expansion of cortical and medullary sinuses restrains lymph node hypertrophy during prolonged inflammation. J. Immunol. 188, 4065–4080 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Roulis, M. et al. Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche. Nature 580, 524–529 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Koliaraki, V., Henriques, A., Prados, A. & Kollias, G. Unfolding innate mechanisms in the cancer microenvironment: the emerging role of the mesenchyme. J. Exp. Med. 217, e20190457 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jacob, N. et al. Inflammation-independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome. Mucosal Immunol. 11, 1466–1476 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Flannigan, K. L., Nieves, K., Alston, L., Mani, S. & Hirota, S. A. Sensing of a microbial metabolite by fibroblasts through the pregnane X receptor restrains inflammation and fibrosis in mice. J. Can. Assoc. Gastroenterol. 2, 30–31 (2019).

    Article  PubMed Central  Google Scholar 

  86. Martin, J. C. et al. Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy. Cell 178, 1493–1508.e20 (2019). A landmark article assessing small-bowel resections from patients with ileal Crohn’s disease alongside paired data from peripheral blood using scRNA-seq.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dennis Jr, G. et al. Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics. Arthritis Res. Ther. 16, R90 (2014).

    Article  CAS  Google Scholar 

  88. Lewis, M. J. et al. Molecular portraits of early rheumatoid arthritis identify clinical and treatment response phenotypes. Cell Rep. 28, 2455–2470.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Buckley, C. D. et al. Persistent induction of the chemokine receptor CXCR4 by TGF-β1 on synovial T cells contributes to their accumulation within the rheumatoid synovium. J. Immunol. 165, 3423–3429 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Bunney, P. E., Zink, A. N., Holm, A. A., Billington, C. J. & Kotz, C. M. Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Physiol. Behav. 176, 139–148 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Firestein, G. S., Alvaro-Gracia, J. M., Maki, R. & Alvaro-Garcia, J. M. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J. Immunol. 144, 3347–3353 (1990).

    Article  CAS  PubMed  Google Scholar 

  92. Pilling, D. et al. Interferon-β mediates stromal cell rescue of T cells from apoptosis. Eur. J. Immunol. 29, 1041–1050 (1999).

    Article  CAS  PubMed  Google Scholar 

  93. Tran, C. N. et al. Molecular interactions between T cells and fibroblast-like synoviocytes role of membrane tumor necrosis factor-on cytokine-activated T cells. Am. J. Pathol. 171, 1588–1598 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Müller-Ladner, U. et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am. J. Pathol. 149, 1607–1615 (1996).

    PubMed  PubMed Central  Google Scholar 

  95. Crowley, T., Buckley, C. D. & Clark, A. R. Stroma: the forgotten cells of innate immune memory. Clin. Exp. Immunol. 193, 24–36 (2018). A review discussing changes in fibroblast properties imprinted by inflammation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ai, R. et al. DNA methylome signature in synoviocytes from patients with early rheumatoid arthritis compared to synoviocytes from patients with longstanding rheumatoid arthritis. Arthritis Rheumatol. 67, 1978–1980 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Firestein, G. S. DNA methylome signature in rheumatoid arthritis. Jpn. J. Clin. Immunol. 35, 367b (2012).

    Article  Google Scholar 

  98. Karouzakis, E. et al. Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis. Sci. Rep. 8, 7370 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Whitaker, J. W. et al. An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. Genome Med. 5, 40 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Barone, F. et al. Stromal fibroblasts in tertiary lymphoid structures: a novel target in chronic inflammation. Front. Immunol. 7, 1–19 (2016).

    Article  CAS  Google Scholar 

  101. Buckley, C. D., Barone, F., Nayar, S., Bénézech, C. & Caamaño, J. Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annu. Rev. Immunol. 33, 715–745 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Cañete, J. D. et al. Ectopic lymphoid neogenesis is strongly associated with activation of the IL-23 pathway in rheumatoid synovitis. Arthritis Res. Therapy 17, 173 (2015).

    Article  CAS  Google Scholar 

  103. Goya, S. et al. Sustained interleukin-6 signalling leads to the development of lymphoid organ-like structures in the lung. J. Pathol. 200, 82–87 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Husson, H. et al. Functional effects of TNF and lymphotoxin α1β2 on FDC-like cells. Cell. Immunol. 203, 134–143 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Lee, J. J. et al. Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. Pneumologie 52, 168 (1998).

    Google Scholar 

  106. Luther, S. A., Ansel, K. M. & Cyster, J. G. Overlapping roles of CXCL13, interleukin 7 receptor α, and CCR7 ligands in lymph node development. J. Exp. Med. 197, 1191–1198 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Nayar, S. et al. Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology. Proc. Natl Acad. Sci. USA 116, 13490–13497 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Barone, F. et al. IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs. Proc. Natl Acad. Sci. USA 112, 11024–11029 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Peduto, L. et al. Inflammation recapitulates the ontogeny of lymphoid stromal cells. J. Immunol. 182, 5789–5799 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Luther, S. A., Lopez, T., Bai, W., Hanahan, D. & Cyster, J. G. BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity 12, 471–481 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Rangel-Moreno, J. et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat. Immunol. 12, 639–646 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wu, Q. et al. Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. J. Exp. Med. 193, 1327–1332 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Link, A. et al. Association of T-zone reticular networks and conduits with ectopic lymphoid tissues in mice and humans. Am. J. Pathol. 178, 1662–1675 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Manzo, A. et al. CCL21 expression pattern of human secondary lymphoid organ stroma is conserved in inflammatory lesions with lymphoid neogenesis. Am. J. Pathol. 171, 1549–1562 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bugatti, S. et al. High expression levels of the B cell chemoattractant CXCL13 in rheumatoid synovium are a marker of severe disease. Rheumatology 53, 1886–1895 (2014).

    Article  CAS  PubMed  Google Scholar 

  116. Cantaert, T. et al. B Lymphocyte autoimmunity in rheumatoid synovitis is independent of ectopic lymphoid neogenesis. J. Immunol. 181, 785–794 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Klimiuk, P. A., Goronzy, J. J., Björnsson, J., Beckenbaugh, R. D. & Weyand, C. M. Tissue cytokine patterns distinguish variants of rheumatoid synovitis. Am. J. Pathol. 151, 1311–1319 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Lanfant-Weybel, K. et al. Synovium CD20 expression is a potential new predictor of bone erosion progression in very-early arthritis treated by sequential DMARDs monotherapy - a pilot study from the VErA cohort. Jt. Bone Spine 79, 574–580 (2012).

    Article  CAS  Google Scholar 

  119. Thurlings, R. M. et al. Synovial lymphoid neogenesis does not define a specific clinical rheumatoid arthritis phenotype. Arthritis Rheum. 58, 1582–1589 (2008).

    Article  PubMed  Google Scholar 

  120. van de Sande, M. G. H. et al. Presence of lymphocyte aggregates in the synovium of patients with early arthritis in relationship to diagnosis and outcome: is it a constant feature over time? Ann. Rheum. Dis. 70, 700–703 (2011).

    Article  PubMed  Google Scholar 

  121. Risselada, A. P., Looije, M. F., Kruize, A. A., Bijlsma, J. W. J. & van Roon, J. A. G. The role of ectopic germinal centers in the immunopathology of primary Sjögren’s syndrome: a systematic review. Semin. Arthritis Rheum. 42, 368–376 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Theander, E. et al. Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren’s syndrome. Ann. Rheum. Dis. 70, 1363–1368 (2011).

    Article  PubMed  Google Scholar 

  123. Sautès-Fridman, C., Petitprez, F., Calderaro, J. & Fridman, W. H. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat. Rev. Cancer 19, 307–325 (2019).

    Article  PubMed  CAS  Google Scholar 

  124. Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020).

    Article  CAS  PubMed  Google Scholar 

  125. Gonzalez, H., Hagerling, C. & Werb, Z. Roles of the immune system in cancer: From tumor initiation t metastatic progression. Genes Dev. 32, 1267–1284 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Dieu-Nosjean, M. C. et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J. Clin. Oncol. 26, 4410–4417 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. Ladányi, A. et al. Density of DC-LAMP+ mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol. Immunother. 56, 1459–1469 (2007).

    Article  PubMed  Google Scholar 

  128. Martinet, L. et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 71, 5678–5687 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. Goc, J. et al. Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Cancer Res. 74, 705–715 (2014).

    Article  CAS  PubMed  Google Scholar 

  130. Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Montfort, A. et al. A strong B-cell response is part of the immune landscape in human high-grade serous ovarian metastases. Clin. Cancer Res. 23, 250–262 (2017).

    Article  CAS  PubMed  Google Scholar 

  132. Germain, C. et al. Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am. J. Respir. Crit. Care Med. 189, 832–844 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Nielsen, J. S. et al. CD20+ tumor-infiltrating lymphocytes have an atypical CD27 - memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin. Cancer Res. 18, 3281–3292 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Schlößer, H. A. et al. B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies. OncoImmunology 8, e1512458 (2019).

    Article  PubMed  Google Scholar 

  135. Chen, L., Qiu, X., Wang, X. & He, J. FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression. Biochem. Biophys. Res. Commun. 487, 8–14 (2017).

    Article  CAS  PubMed  Google Scholar 

  136. Cohen, N. et al. Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of chitinase 3-like 1. Oncogene 36, 4457–4468 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Comito, G. et al. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene 33, 2423–2431 (2014).

    Article  CAS  PubMed  Google Scholar 

  138. Gunderson, A. J. et al. Blockade of fibroblast activation protein in combination with radiation treatment in murine models of pancreatic adenocarcinoma. PLoS ONE 14, e0211117 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ksiazkiewicz, M. et al. Importance of CCL2-CCR2A/2B signaling for monocyte migration into spheroids of breast cancer-derived fibroblasts. Immunobiology 215, 737–747 (2010).

    Article  CAS  PubMed  Google Scholar 

  140. Pautu, J. L. & Kumar, L. Intratumoral T cells and survival in epithelial ovarian cancer. Natl Med. J. India 16, 150–151 (2003).

    PubMed  Google Scholar 

  141. Azimi, F. et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J. Clin. Oncol. 30, 2678–2683 (2012).

    Article  PubMed  Google Scholar 

  142. Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Gorchs, L. et al. Human pancreatic carcinoma-associated fibroblasts promote expression of co-inhibitory markers on CD4+ and CD8+ T-cells. Front. Immunol. 10, 847 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lakins, M. A., Ghorani, E., Munir, H., Martins, C. P. & Shields, J. D. Cancer-associated fibroblasts induce antigen-specific deletion of CD8+ T cells to protect tumour cells. Nat. Commun. 9, 948 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Hsu, Y. L. et al. Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis. Oncotarget 7, 27584–27598 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Xiao, Q. et al. Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation. Cancer Res. 76, 5395–5404 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Vizoso, M. et al. Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts. Carcinogenesis 36, 1453–1463 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Albrengues, J. et al. Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat. Commun. 6, 10204 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. Direkze, N. C. et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res. 64, 8492–8495 (2004).

    Article  CAS  PubMed  Google Scholar 

  151. Hosaka, K. et al. Pericyte-fibroblast transition promotes tumor growth and metastasis. Proc. Natl Acad. Sci. USA 113, E5618–E5627 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ishii, G. et al. In vivo characterization of bone marrow-derived fibroblasts recruited into fibrotic lesions. Stem Cell 23, 699–706 (2005).

    Article  CAS  Google Scholar 

  153. Petersen, O. W. et al. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am. J. Pathol. 162, 391–402 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Quante, M. et al. Bone marrow-derived myofibroblasts contribute to the growth MSC niche and promote tumour growth. Cancer Cell 19, 257–272 (2012).

    Article  CAS  Google Scholar 

  155. Zeisberg, E. M., Potenta, S., Xie, L., Zeisberg, M. & Kalluri, R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67, 10123–10128 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Raz, Y. et al. Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer. J. Exp. Med. 215, 3075–3093 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Efremova, M., Vento-Tormo, M., Teichmann, S. A. & Vento-Tormo, R. CellPhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes. Nat. Protoc. 15, 1484–1506 (2020). CellPhoneDB performs ligand–receptor analysis on datasets, from which interactions between different cell types can be inferred.

    Article  CAS  PubMed  Google Scholar 

  158. Browaeys, R., Saelens, W. & Saeys, Y. NicheNet: modeling intercellular communication by linking ligands to target genes. Nat. Methods 17, 159–162 (2020). NicheNet is another computational tool that can predict interactions between cell types, as well as the effects of particular ligands on gene expression in responding cells.

    Article  CAS  PubMed  Google Scholar 

  159. Duperret, E. K. et al. Alteration of the tumor stroma using a consensus DNA vaccine targeting fibroblast activation protein (FAP) synergizes with antitumor vaccine therapy in Mice. Clin. Cancer Res. 24, 1190–1201 (2018).

    Article  CAS  PubMed  Google Scholar 

  160. Fang, J. et al. A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice. Int. J. Cancer 138, 1013–1023 (2016).

    Article  CAS  PubMed  Google Scholar 

  161. Loeffler, M., Krüger, J. A., Niethammer, A. G. & Reisfeld, R. A. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J. Clin. Invest. 116, 1955–1962 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Ostermann, E. et al. Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin. Cancer Res. 14, 4584–4592 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. Wang, L. C. S. et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol. Res. 2, 154–166 (2014).

    Article  CAS  PubMed  Google Scholar 

  164. Roberts, E. W. et al. Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia. J. Exp. Med. 210, 1137–1151 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Özdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Calon, A. et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Ohshio, Y. et al. Cancer-associated fibroblast-targeted strategy enhances antitumor immune responses in dendritic cell-based vaccine. Cancer Sci. 106, 134–142 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Takai, K., Le, A., Weaver, V. M. & Werb, Z. Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget 7, 82889–82901 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Bai, Y. P. et al. FGF-1/-3/FGFR4 signaling in cancer-associated fibroblasts promotes tumor progression in colon cancer through Erk and MMP-7. Cancer Sci. 106, 1278–1287 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Sherman, M. H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Katoh, M. FGFR inhibitors: effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). Int. J. Mol. Med. 38, 3–15 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Richeldi, L. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 370, 2071–2082 (2014).

    Article  PubMed  CAS  Google Scholar 

  174. Tan, H.-Y. et al. Targeting tumour microenvironment by tyrosine kinase inhibitor. Mol. Cancer 17, 43 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Alivernini, S. et al. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat. Med. 26, 1295–1306 (2020). A key article identifying unique macrophage populations enriched in RA, resolution and flare. These populations are involved in complex crosstalk with joint fibroblasts.

    Article  CAS  PubMed  Google Scholar 

  176. Atreya, R. et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat. Med. 6, 583–588 (2000).

    Article  CAS  PubMed  Google Scholar 

  177. Danese, S. et al. Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II). Gut 68, 40–48 (2019).

    Article  CAS  PubMed  Google Scholar 

  178. Gout, T., Östör, A. J. K. & Nisar, M. K. Lower gastrointestinal perforation in rheumatoid arthritis patients treated with conventional DMARDs or tocilizumab: a systematic literature review. Clin. Rheumatol. 30, 1471–1474 (2011).

    Article  PubMed  Google Scholar 

  179. Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Elson, C. O. et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 132, 2359–2370 (2007).

    Article  CAS  PubMed  Google Scholar 

  181. Yen, D. et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo- controlled trial. Gut 61, 1693–1700 (2012).

    Article  CAS  PubMed  Google Scholar 

  183. Targan, S. R. et al. A randomized, double-blind, placebo-controlled phase 2 study of brodalumab in patients with moderate-to-severe Crohn’s disease. Am. J. Gastroenterol. 111, 1599–1607 (2016).

    Article  CAS  PubMed  Google Scholar 

  184. Al-Sadi, R. et al. Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway. PLoS ONE 9, e85345 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Lee, J. S. et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43, 727–738 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge discussions with members of the Buckley–Coles laboratory in Oxford and Birmingham and with M. Pohin and M. Friedrich at the Kennedy Institute.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christopher D. Buckley.

Ethics declarations

Competing interests

C.D.B., M.B. and M.C. are founders of Mestag Therapeutics, a company that aims to discover, develop and deliver impactful precision medicines through targeting disease-driving fibroblast subpopulations. B.L. is a founder of Stromal Therapeutics. S.T. is employed by Genentech.

Additional information

Peer review information

Nature Reviews Immunology thanks J. Cyster, R. Flavell, G. Schett and the other, anonymous, reviewer for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

HOX genes

A group genes encoding homeobox transcription factors that specify the location, orientation and patterning of tissues during development.

WNT pathway

A signalling pathway that regulates cell fate determination, proliferation, adhesion, migration and polarity during development. In addition to the crucial role of this pathway in embryogenesis, WNT ligands and their downstream signalling molecules have been implicated in tumorigenesis and have causative roles in human colon cancers.

Hepatic stellate cells

Also known as Ito cells, these are types of pericytes found in the hepatic perisinusoidal space that are the main reservoirs of retinol in the liver.

Myofibroblast

A cell type with an activated fibroblast phenotype that is enriched in pathology. Myofibroblasts are often characterized by expression of α-smooth musle actin and increased cytoskeletal contraction.

YAP and TAZ

Transcription factors that are phosphorylated in the Hippo signalling pathway, which is an evolutionarily conserved pathway, controlling organ size by regulating cell apoptosis and proliferation. Whereas phosphorylation of these factors prevents their entry into the nucleus, dephosphorylation activates them. Dysregulation of this pathway has been identified in cancer.

Triple-negative breast cancers

A subtype of breast cancer that lacks expression of human epidermal growth factor receptor 2 (HER2), oestrogen receptors and progesterone receptors. As a result, there are limited treatment options for this breast cancer type.

Luminal breast cancers

A subset of breast cancers positive for oestrogen receptors and/or progesterone receptors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Davidson, S., Coles, M., Thomas, T. et al. Fibroblasts as immune regulators in infection, inflammation and cancer. Nat Rev Immunol 21, 704–717 (2021). https://doi.org/10.1038/s41577-021-00540-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-021-00540-z

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer