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:

The mesenchymal context in inflammation, immunity and cancer

Nature Immunology volume 21, pages 974–982 (2020)Cite this article

Subjects

Abstract

Mesenchymal cells are mesoderm-derived stromal cells that are best known for providing structural support to organs, synthesizing and remodeling the extracellular matrix (ECM) and regulating development, homeostasis and repair of tissues. Recent detailed mechanistic insights into the biology of fibroblastic mesenchymal cells have revealed they are also significantly involved in immune regulation, stem cell maintenance and blood vessel function. It is now becoming evident that these functions, when defective, drive the development of complex diseases, such as various immunopathologies, chronic inflammatory disease, tissue fibrosis and cancer. Here, we provide a concise overview of the contextual contribution of fibroblastic mesenchymal cells in physiology and disease and bring into focus emerging evidence for both their heterogeneity at the single-cell level and their tissue-specific, spatiotemporal functional diversity.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Homeostatic roles of mesenchymal cells.
Fig. 2: Mesenchymal cells in immunity.
Fig. 3: Resident mesenchymal cells in wound healing, inflammation and fibrosis.
Fig. 4: Mesenchymal cells in cancer.

Similar content being viewed by others

References

  1. LeBleu, V. S. & Neilson, E. G. Origin and functional heterogeneity of fibroblasts. FASEB J. 34, 3519–3536 (2020).

    CAS  PubMed  Google Scholar 

  2. Lemos, D. R. & Duffield, J. S. Tissue-resident mesenchymal stromal cells: implications for tissue-specific antifibrotic therapies. Sci. Transl. Med. 10, eaan5174 (2018).

    PubMed  Google Scholar 

  3. Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

    CAS  PubMed  Google Scholar 

  4. Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 15, 786–801 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Buechler, M. B. & Turley, S. J. A short field guide to fibroblast function in immunity. Semin. Immunol. 35, 48–58 (2018).

    CAS  PubMed  Google Scholar 

  6. Perez-Shibayama, C., Gil-Cruz, C. & Ludewig, B. Fibroblastic reticular cells at the nexus of innate and adaptive immune responses. Immunol. Rev. 289, 31–41 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Armulik, A., Genové, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

    CAS  PubMed  Google Scholar 

  8. Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G. & Morrison, S. J. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15, 154–168 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Guimarães-Camboa, N. et al. Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell 20, 345–359.e5 (2017).

    PubMed  PubMed Central  Google Scholar 

  10. Worthley, D. L. et al. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 160, 269–284 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Sacchetti, B. et al. No identical “mesenchymal stem cells” at different times and sites: human committed progenitors of distinct origin and differentiation potential are incorporated as adventitial cells in microvessels. Stem Cell Rep. 6, 897–913 (2016).

    CAS  Google Scholar 

  12. Stzepourginski, I. et al. CD34+ mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury. Proc. Natl Acad. Sci. USA 114, E506–E513 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sennett, R. & Rendl, M. Mesenchymal–epithelial interactions during hair follicle morphogenesis and cycling. Semin. Cell Dev. Biol. 23, 917–927 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee, J.-H. et al. Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6. Cell 170, 1149–1163.e12 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sanders, K. M., Ward, S. M. & Koh, S. D. Interstitial cells: regulators of smooth muscle function. Physiol. Rev. 94, 859–907 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Firestein, G. S., Budd, R. C., Gabriel, S. E., McInnes, I. B. & O’Dell, J. R. Kelley and Firestein’s Textbook of Rheumatology, 10th edn (Elsevier, 2016).

  18. 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).

    PubMed  PubMed Central  Google Scholar 

  19. Beachley, V. Z. et al. Tissue matrix arrays for high throughput screening and systems analysis of cell function. Nat. Methods 12, 1197–1204 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Driskell, R. R. et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277–281 (2013). This study showed how different mesenchymal lineages orchestrate skin development and repair.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Xie, T. et al. Single-cell deconvolution of fibroblast heterogeneity in mouse pulmonary fibrosis. Cell Rep. 22, 3625–3640 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Guo, M. et al. Single cell RNA analysis identifies cellular heterogeneity and adaptive responses of the lung at birth. Nat. Commun. 10, 37 (2019).

    PubMed  PubMed Central  Google Scholar 

  24. Pinho, S. & Frenette, P. S. Haematopoietic stem cell activity and interactions with the niche. Nat. Rev. Mol. Cell Biol. 20, 303–320 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Krishnamurty, A. T. & Turley, S. J. Lymph node stromal cells: cartographers of the immune system. Nat. Immunol. 21, 369–380 (2020).

    CAS  PubMed  Google Scholar 

  26. Rodda, L. B. et al. Single-cell RNA sequencing of lymph node stromal cells reveals niche-associated heterogeneity. Immunity 48, 1014–1028.e16 (2018). The first single-cell RNA sequencing analysis of murine lymph nodes, which identified novel SLO-MC populations.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Baryawno, N. et al. A cellular taxonomy of the bone marrow stroma in homeostasis and leukemia. Cell 177, 1915–1932.e16 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Denton, A. E., Carr, E. J., Magiera, L. P., Watts, A. J. B. & Fearon, D. T. Embryonic FAP+ lymphoid tissue organizer cells generate the reticular network of adult lymph nodes. J. Exp. Med. 216, 2242–2252 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cheng, H.-W. et al. Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp. Nat. Commun. 10, 1739 (2019).

    PubMed  PubMed Central  Google Scholar 

  31. Mendez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Greenbaum, A. et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495, 227–230 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ding, L., Saunders, T. L., Enikolopov, G. & Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kunisaki, Y. et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502, 637–643 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Comazzetto, S. et al. Restricted hematopoietic progenitors and erythropoiesis require SCF from leptin receptor+ niche cells in the bone marrow. Cell Stem Cell 24, 477–486.e6 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Khan, J. A. et al. Fetal liver hematopoietic stem cell niches associate with portal vessels. Science 351, 176–180 (2016).

    CAS  PubMed  Google Scholar 

  37. Sun, L. et al. FSP1+ fibroblast subpopulation is essential for the maintenance and regeneration of medullary thymic epithelial cells. Sci. Rep. 5, 14871 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sitnik, K. M. et al. Mesenchymal cells regulate retinoic acid receptor-dependent cortical thymic epithelial cell homeostasis. J. Immunol. 188, 4801–4809 (2012).

    CAS  PubMed  Google Scholar 

  39. Park, J.-E. et al. A cell atlas of human thymic development defines T cell repertoire formation. Science 367, eaay3224 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Schulz, O., Hammerschmidt, S. I., Moschovakis, G. L. & Förster, R. Chemokines and chemokine receptors in lymphoid tissue dynamics. Annu. Rev. Immunol. 34, 203–242 (2016).

    CAS  PubMed  Google Scholar 

  41. Lu, E., Wolfreys, F. D., Muppidi, J. R., Xu, Y. & Cyster, J. G. S-Geranylgeranyl-l-glutathione is a ligand for human B cell-confinement receptor P2RY8. Nature 567, 244–248 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Bénézech, C. et al. Ontogeny of stromal organizer cells during lymph node development. J. Immunol. 184, 4521–4530 (2010).

    PubMed  Google Scholar 

  43. Magri, G. et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat. Immunol. 15, 354–364 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Camara, A. et al. Lymph node mesenchymal and endothelial stromal cells cooperate via the RANK-RANKL cytokine axis to shape the sinusoidal macrophage niche. Immunity 50, 1467–1481.e6 (2019).

    CAS  PubMed  Google Scholar 

  45. Nagashima, K. et al. Identification of subepithelial mesenchymal cells that induce IgA and diversify gut microbiota. Nat. Immunol. 18, 675–682 (2017). This study revealed how SLO-MCs induce epithelial differentiation and affect microbiota composition.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Dubey, L. K., Ludewig, B., Luther, S. A. & Harris, N. L. IL-4Rα-expressing B cells are required for CXCL13 production by fibroblastic reticular cells. Cell Rep. 27, 2442–2458.e5 (2019).

    CAS  PubMed  Google Scholar 

  48. Heesters, B. A., Myers, R. C. & Carroll, M. C. Follicular dendritic cells: dynamic antigen libraries. Nat. Rev. Immunol. 14, 495–504 (2014).

    CAS  PubMed  Google Scholar 

  49. van der Poel, C. E. et al. Follicular dendritic cells modulate germinal center B cell diversity through FcγRIIB. Cell Rep. 29, 2745–2755.e4 (2019).

    PubMed  PubMed Central  Google Scholar 

  50. Zhang, Y. et al. Plasma cell output from germinal centers is regulated by signals from Tfh and stromal cells. J. Exp. Med. 215, 1227–1243 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Brown, F. D. et al. Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling. Nat. Immunol. 20, 1668–1680 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Chang, J. E., Buechler, M. B., Gressier, E., Turley, S. J. & Carroll, M. C. Mechanosensing by Peyer’s patch stroma regulates lymphocyte migration and mucosal antibody responses. Nat. Immunol. 20, 1506–1516 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Gil-Cruz, C. et al. Fibroblastic reticular cells regulate intestinal inflammation via IL-15-mediated control of group 1 ILCs. Nat. Immunol. 17, 1388–1396 (2016). This study revealed the capacity of FRCs to sense innate signals and regulate immune functions.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 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).

    CAS  PubMed  Google Scholar 

  56. Bonnardel, J. et al. Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity 51, 638–654.e9 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Buechler, M. B. et al. A stromal niche defined by expression of the transcription factor WT1 mediates programming and homeostasis of cavity-resident macrophages. Immunity 51, 119–130.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Vicente-Suarez, I. et al. Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells. Mucosal Immunol. 8, 141–151 (2015).

    CAS  PubMed  Google Scholar 

  59. Dahlgren, M. W. et al. Adventitial stromal cells define group 2 innate lymphoid cell tissue niches. Immunity 50, 707–722.e6 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Mahlakõiv, T. et al. Stromal cells maintain immune cell homeostasis in adipose tissue via production of interleukin-33. Sci. Immunol. 4, eaax0416 (2019).

    PubMed  PubMed Central  Google Scholar 

  61. Spallanzani, R. G. et al. Distinct immunocyte-promoting and adipocyte-generating stromal components coordinate adipose tissue immune and metabolic tenors. Sci. Immunol. 4, eaaw3658 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Oherle, K. et al. Insulin-like growth factor 1 supports a pulmonary niche that promotes type 3 innate lymphoid cell development in newborn lungs. Immunity 52, 275–294.e9 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Nowarski, R., Jackson, R. & Flavell, R. A. The stromal intervention: regulation of immunity and inflammation at the epithelial-mesenchymal barrier. Cell 168, 362–375 (2017).

    CAS  PubMed  Google Scholar 

  64. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Armaka, M., Ospelt, C., Pasparakis, M. & Kollias, G. The p55TNFR-IKK2-Ripk3 axis orchestrates arthritis by regulating death and inflammatory pathways in synovial fibroblasts. Nat. Commun. 9, 618 (2018).

    PubMed  PubMed Central  Google Scholar 

  66. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Roulis, M. et al. Intestinal myofibroblast-specific Tpl2-Cox-2-PGE2 pathway links innate sensing to epithelial homeostasis. Proc. Natl Acad. Sci. USA 111, E4658–E4667 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730.e22 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Kinchen, J. et al. Structural remodeling of the human colonic mesenchyme in inflammatory bowel disease. Cell 175, 372–386.e17 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Vomero, M. et al. Autophagy and rheumatoid arthritis: current knowledges and future perspectives. Front. Immunol. 9, 1577 (2018).

    PubMed  PubMed Central  Google Scholar 

  74. Montero-Melendez, T. et al. Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis. Nat. Commun. 11, 745 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019). This study reported striking phenotypic differences between SF subpopulations in silico and in vivo, illustrating the impact of SF heterogeneity in disease progression.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789 (2018).

    PubMed  PubMed Central  Google Scholar 

  77. 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).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Di Carlo, S. E. & Peduto, L. The perivascular origin of pathological fibroblasts. J. Clin. Invest. 128, 54–63 (2018).

    PubMed  PubMed Central  Google Scholar 

  80. Guerrero-Juarez, C. F. et al. Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds. Nat. Commun. 10, 650 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Rinkevich, Y. et al. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science 348, aaa2151 (2015). This study identified and analyzed a specific dermal lineage with important functions in fibrosis.

    PubMed  PubMed Central  Google Scholar 

  82. Correa-Gallegos, D. et al. Patch repair of deep wounds by mobilized fascia. Nature 576, 287–292 (2019).

    CAS  PubMed  Google Scholar 

  83. Coppé, J.-P., Desprez, P.-Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).

    PubMed  PubMed Central  Google Scholar 

  84. Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Shook, B. A. et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science 362, eaar2971 (2018).

    PubMed  PubMed Central  Google Scholar 

  86. Salzer, M. C. et al. Identity noise and adipogenic traits characterize dermal fibroblast aging. Cell 175, 1575–1590.e22 (2018).

    CAS  PubMed  Google Scholar 

  87. Mahmoudi, S. et al. Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing. Nature 574, 553–558 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Ng, B. et al. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Sci. Transl. Med. 11, eaaw1237 (2019).

    CAS  PubMed  Google Scholar 

  90. Widjaja, A. A. et al. Inhibiting interleukin 11 signaling reduces hepatocyte death and liver fibrosis, inflammation, and steatosis in mouse models of nonalcoholic steatohepatitis. Gastroenterology 157, 777–792.e14 (2019).

    CAS  PubMed  Google Scholar 

  91. Liu, F. et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am. J. Physiol. Lung Cell Mol. Physiol. 308, L344–L357 (2015).

    CAS  Google Scholar 

  92. Wohlfahrt, T. et al. PU.1 controls fibroblast polarization and tissue fibrosis. Nature 566, 344–349 (2019). This study showed how inhibition of a new mesenchymal-specific molecular mechanism that drives fibrosis can actually lead to fibrosis regression.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Glasser, S. W. et al. Mechanisms of lung fibrosis resolution. Am. J. Pathol. 186, 1066–1077 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Peyser, R. et al. Defining the activated fibroblast population in lung fibrosis using single-cell sequencing. Am. J. Respir. Cell Mol. Biol. 61, 74–85 (2019).

    CAS  PubMed  Google Scholar 

  95. El Agha, E. et al. Two-way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis. Cell Stem Cell 20, 261–273.e3 (2017).

    CAS  PubMed  Google Scholar 

  96. Hung, C. et al. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 188, 820–830 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Aran, D. et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat. Immunol. 20, 163–172 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Gieniec, K. A., Butler, L. M., Worthley, D. L. & Woods, S. L. Cancer-associated fibroblasts—heroes or villains? Br. J. Cancer 121, 293–302 (2019).

    PubMed  PubMed Central  Google Scholar 

  102. 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).

    PubMed  PubMed Central  Google Scholar 

  103. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Li, H. et al. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat. Genet. 49, 708–718 (2017).

    CAS  PubMed  Google Scholar 

  105. 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). Along with other mechanistic studies from this group, this study provided a detailed analysis of the functional properties of CAF subpopulations in PDAC.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  108. Ollila, S. et al. Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway. J. Clin. Invest. 128, 402–414 (2018).

    PubMed  Google Scholar 

  109. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Calon, A. et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat. Genet. 47, 320–329 (2015).

    CAS  PubMed  Google Scholar 

  111. Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).

    CAS  PubMed  Google Scholar 

  112. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018). This study and the study by Tauriello et al. identified a crucial mechanism through which CAFs affect the response to immunotherapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. He, Z. et al. Interleukin 1 beta and matrix metallopeptidase 3 contribute to development of epidermal growth factor receptor–dependent serrated polyps in mouse cecum. Gastroenterology 157, 1572–1583.e8 (2019).

    CAS  PubMed  Google Scholar 

  114. Erez, N., Truitt, M., Olson, P., Arron, S. T. & 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).

    CAS  PubMed  Google Scholar 

  115. 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).

    PubMed  Google Scholar 

  116. Koliaraki, V. et al. Innate sensing through mesenchymal TLR4/MyD88 signals promotes spontaneous intestinal tumorigenesis. Cell Rep. 26, 536–545.e4 (2019). This study provided in vivo evidence for the protumorigenic innate immune activation of CAFs in intestinal cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Ershaid, N. et al. NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis. Nat. Commun. 10, 4375 (2019).

    PubMed  PubMed Central  Google Scholar 

  118. Heichler, C. et al. STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis. Gut 69, 1269–1282 (2019).

    PubMed  Google Scholar 

  119. Labernadie, A. et al. A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nat. Cell Biol. 19, 224–237 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Mohammadi, H. & Sahai, E. Mechanisms and impact of altered tumour mechanics. Nat. Cell Biol. 20, 766–774 (2018).

    CAS  PubMed  Google Scholar 

  121. Yan, W. et al. Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nat. Cell Biol. 20, 597–609 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Fu, Y. et al. The reverse Warburg effect is likely to be an Achilles’ heel of cancer that can be exploited for cancer therapy. Oncotarget 8, 57813–57825 (2017).

    PubMed  PubMed Central  Google Scholar 

  123. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Salmon, H. et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 122, 899–910 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Chakravarthy, A., Khan, L., Bensler, N. P., Bose, P. & De Carvalho, D. D. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat. Commun. 9, 4692 (2018).

    PubMed  PubMed Central  Google Scholar 

  126. Wang, L. et al. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nat. Commun. 9, 3503 (2018).

    PubMed  PubMed Central  Google Scholar 

  127. Kumar, V. et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32, 654–668.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Öhlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017).

    PubMed  PubMed Central  Google Scholar 

  129. Neuzillet, C. et al. Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma. J. Pathol. 248, 51–65 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  131. 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).

    PubMed  PubMed Central  Google Scholar 

  132. Dominguez, C. X. et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov. 10, 232–253 (2020).

    PubMed  Google Scholar 

  133. Kobayashi, H. et al. Cancer-associated fibroblasts in gastrointestinal cancer. Nat. Rev. Gastroenterol. Hepatol. 16, 282–295 (2019).

    PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the co-organizers, presenters and attendees of the EMBO meeting “Mesenchymal Cells in Immunity, Inflammation and Cancer”, held in Athens in 2019, for insightful discussions on mesenchymal cells. This work was supported by a grant from the Stavros Niarchos Foundation to the BSRC ‘Alexander Fleming’’ as part of the Foundation’s initiative to support the Greek research center ecosystem, and the FP7 Advanced ERC Grant MCs-inTEST (grant 340217) to G.K.

Author information

Authors and Affiliations

  1. Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center “Alexander Fleming”, Vari, Greece

    Vasiliki Koliaraki, Marietta Armaka & George Kollias

  2. Institute for Bioinnovation, Biomedical Sciences Research Center “Alexander Fleming”, Vari, Greece

    Alejandro Prados & George Kollias

  3. Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    George Kollias

Authors
  1. Vasiliki Koliaraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alejandro Prados
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marietta Armaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George Kollias
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Vasiliki Koliaraki or George Kollias.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Editor recognition statement L. A. Dempsey was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koliaraki, V., Prados, A., Armaka, M. et al. The mesenchymal context in inflammation, immunity and cancer. Nat Immunol 21, 974–982 (2020). https://doi.org/10.1038/s41590-020-0741-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-020-0741-2

This article is cited by

Search

Advanced 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