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.

  • Perspective
  • Published:

The advent of immune stimulating CAFs in cancer

Nature Reviews Cancer volume 23, pages 258–269 (2023)Cite this article

Subjects

Abstract

The theory that cancer-associated fibroblasts (CAFs) are immunosuppressive cells has prevailed throughout the past decade. However, recent high-throughput, high-resolution mesenchyme-directed single-cell studies have harnessed computational advances to functionally characterize cell states, highlighting the existence of immunostimulatory CAFs. Our group and others have uncovered and experimentally substantiated key functions of cancer antigen-presenting CAFs in T cell immunity, both in vitro and in vivo, refuting the conventional assumption that CAFs impede adaptive immune rejection of tumours. In this Perspective, I unify the follicular and non-follicular, non-endothelial stroma of tumours under the ‘peripheral adaptive immune mesenchyme’ framework and position subsets of CAFs as direct positive regulators of the adaptive immune system. Building on the understanding of cancer antigen presentation by CAFs and the second touch hypothesis, which postulates that full T cell polarization requires interaction with antigen-presenting cells in the non-lymphoid tissue where the antigen resides, I re-design the ‘cancer-immunity cycle’ to incorporate intratumoural activation of cancer-specific CD4+ T cells. Lastly, a road map to therapeutic harnessing of immunostimulatory CAF states is proposed.

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: The central and peripheral adaptive immune mesenchyme.
Fig. 2: Immune stimulating cancer-associated fibroblasts.
Fig. 3: Reworked model of the second touch hypothesis in the cancer-immunity cycle.

Similar content being viewed by others

References

  1. Davidson, S. et al. Fibroblasts as immune regulators in infection, inflammation and cancer. Nat. Rev. Immunol. 21, 704–717 (2021).

    Article  CAS  PubMed  Google Scholar 

  2. Koliaraki, V., Prados, A., Armaka, M. & Kollias, G. The mesenchymal context in inflammation, immunity and cancer. Nat. Immunol. 21, 974–982 (2020).

    Article  CAS  PubMed  Google Scholar 

  3. Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Biffi, G. & Tuveson, D. A. Diversity and biology of cancer-associated fibroblasts. Physiol. Rev. 101, 147–176 (2021).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mhaidly, R. & Mechta-Grigoriou, F. Role of cancer-associated fibroblast subpopulations in immune infiltration, as a new means of treatment in cancer. Immunol. Rev. 302, 259–272 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Barrett, R. & Pure, E. Cancer-associated fibroblasts: key determinants of tumor immunity and immunotherapy. Curr. Opin. Immunol. 64, 80–87 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang, Y. & Ertl, H. C. Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+ T cells within tumors. Oncotarget 7, 23282–23299 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lo, A. et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 75, 2800–2810 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rozenblatt-Rosen, O. et al. The Human Tumor Atlas Network: charting tumor transitions across space and time at single-cell resolution. Cell 181, 236–249 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zeng, J. et al. CancerSCEM: a database of single-cell expression map across various human cancers. Nucleic Acids Res. 50, D1147–D1155 (2022).

    Article  CAS  PubMed  Google Scholar 

  12. Waise, S. et al. An optimised tissue disaggregation and data processing pipeline for characterising fibroblast phenotypes using single-cell RNA sequencing. Sci. Rep. 9, 9580 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Slyper, M. et al. A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors. Nat. Med. 26, 792–802 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen, Y. et al. Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer Cell 39, 548–565.e6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ozdemir, 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  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hu, H. et al. Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms. Cancer Cell 39, 1531–1547.e10 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Friedman, G. et al. Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4+ and PDPN+ CAFs to clinical outcome. Nat. Cancer 1, 692–708 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. Grauel, A. L. et al. TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts. Nat. Commun. 11, 6315 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kerdidani, D. et al. Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts. J. Exp. Med. 219, e20210815 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hutton, C. et al. Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity. Cancer Cell 39, 1227–1244.e20 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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 

  22. 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).

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. 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  Google Scholar 

  25. 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 

  26. Baker, A. T., Abuwarwar, M. H., Poly, L., Wilkins, S. & Fletcher, A. L. Cancer-associated fibroblasts and T cells: from mechanisms to outcomes. J. Immunol. 206, 310–320 (2021).

    Article  CAS  PubMed  Google Scholar 

  27. Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

    Article  PubMed  Google Scholar 

  28. Ley, K. The second touch hypothesis: T cell activation, homing and polarization. F1000Res 3, 37 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Itano, A. A. & Jenkins, M. K. Antigen presentation to naive CD4 T cells in the lymph node. Nat. Immunol. 4, 733–739 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Jenkins, M. K., Chen, C. A., Jung, G., Mueller, D. L. & Schwartz, R. H. Inhibition of antigen-specific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3 monoclonal antibody. J. Immunol. 144, 16–22 (1990).

    Article  CAS  PubMed  Google Scholar 

  32. Harding, F. A., McArthur, J. G., Gross, J. A., Raulet, D. H. & Allison, J. P. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 356, 607–609 (1992).

    Article  CAS  PubMed  Google Scholar 

  33. Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5, 987–995 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Mescher, M. F. et al. Signals required for programming effector and memory development by CD8+ T cells. Immunol. Rev. 211, 81–92 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. 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 

  38. Baccin, C. et al. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat. Cell Biol. 22, 38–48 (2020).

    Article  CAS  PubMed  Google Scholar 

  39. Asada, N. et al. Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nat. Cell Biol. 19, 214–223 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Robinson, M. J., Webster, R. H. & Tarlinton, D. M. How intrinsic and extrinsic regulators of plasma cell survival might intersect for durable humoral immunity. Immunol. Rev. 296, 87–103 (2020).

    Article  CAS  PubMed  Google Scholar 

  41. Li, K. L., Li, J. Y., Xie, G. L. & Ma, X. Y. Exosomes released from human bone marrow-derived mesenchymal stem cell attenuate acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in mice. Front. Cell Dev. Biol. 9, 617589 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Galipeau, J. & Sensebe, L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 22, 824–833 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. 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 

  45. Nitta, T. et al. Fibroblasts as a source of self-antigens for central immune tolerance. Nat. Immunol. 21, 1172–1180 (2020).

    Article  PubMed  Google Scholar 

  46. Prados, A. et al. Fibroblastic reticular cell lineage convergence in Peyer’s patches governs intestinal immunity. Nat. Immunol. 22, 510–519 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Alexandre, Y. O. et al. A diverse fibroblastic stromal cell landscape in the spleen directs tissue homeostasis and immunity. Sci. Immunol. 7, eabj0641 (2022).

    Article  CAS  PubMed  Google Scholar 

  48. Schaeuble, K. et al. Perivascular fibroblasts of the developing spleen act as Ltα1β2-dependent precursors of both T and B zone organizer cells. Cell Rep. 21, 2500–2514 (2017).

    Article  CAS  PubMed  Google Scholar 

  49. 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 

  50. Heesters, B. A. et al. Characterization of human FDCs reveals regulation of T cells and antigen presentation to B cells. J. Exp. Med. 218, e20210790 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fletcher, A. L., Acton, S. E. & Knoblich, K. Lymph node fibroblastic reticular cells in health and disease. Nat. Rev. Immunol. 15, 350–361 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  54. 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 

  55. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kapoor, V. N. et al. Gremlin 1+ fibroblastic niche maintains dendritic cell homeostasis in lymphoid tissues. Nat. Immunol. 22, 571–585 (2021).

    Article  CAS  PubMed  Google Scholar 

  58. 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 

  59. Kim, D. et al. Lymph node fibroblastic reticular cells regulate differentiation and function of CD4 T cells via CD25. J. Exp. Med. 219 (2022).

  60. Dubrot, J. et al. Lymph node stromal cells acquire peptide–MHCII complexes from dendritic cells and induce antigen-specific CD4+ T cell tolerance. J. Exp. Med. 211, 1153–1166 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Baptista, A. P. et al. Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation. eLife 3, e04433 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Nadafi, R. et al. Lymph node stromal cells generate antigen-specific regulatory T cells and control autoreactive T and B cell responses. Cell Rep. 30, 4110–4123.e4 (2020).

    Article  CAS  PubMed  Google Scholar 

  63. Kumar, V. et al. A dendritic-cell–stromal axis maintains immune responses in lymph nodes. Immunity 42, 719–730 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Huang, H. Y. et al. Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis. Proc. Natl Acad. Sci. USA 115, E6826–E6835 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dasoveanu, D. C. et al. Lymph node stromal CCL2 limits antibody responses. Sci. Immunol. 5, eaaw0693 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Buechler, M. B. et al. Cross-tissue organization of the fibroblast lineage. Nature 593, 575–579 (2021).

    Article  CAS  PubMed  Google Scholar 

  68. Korsunsky, I. et al. Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med 3, 481–518.e14 (2022).

    Article  CAS  PubMed  Google Scholar 

  69. Nayar, S. et al. Immunofibroblasts regulate Ltα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction. Commun. Biol. 5, 413 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Noack, M. & Miossec, P. Importance of lymphocyte–stromal cell interactions in autoimmune and inflammatory rheumatic diseases. Nat. Rev. Rheumatol. 17, 550–564 (2021).

    Article  CAS  PubMed  Google Scholar 

  71. Xu, Z. et al. Anatomically distinct fibroblast subsets determine skin autoimmune patterns. Nature 601, 118–124 (2022).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. McKinney, E. F., Lee, J. C., Jayne, D. R., Lyons, P. A. & Smith, K. G. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 523, 612–616 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mourcin, F. et al. Follicular lymphoma triggers phenotypic and functional remodeling of the human lymphoid stromal cell landscape. Immunity 54, 1901 (2021).

    Article  CAS  PubMed  Google Scholar 

  75. Barone, F. et al. Stromal fibroblasts in tertiary lymphoid structures: a novel target in chronic inflammation. Front. Immunol. 7, 477 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Schumacher, T. N. & Thommen, D. S. Tertiary lymphoid structures in cancer. Science 375, eabf9419 (2022).

    Article  CAS  PubMed  Google Scholar 

  77. Grout, J. A. et al. Spatial positioning and matrix programs of cancer-associated fibroblasts promote T-cell exclusion in human lung tumors. Cancer Discov. 12, 2606–2625 (2022).

    Article  CAS  PubMed  Google Scholar 

  78. Du Bois, H., Heim, T. A. & Lund, A. W. Tumor-draining lymph nodes: at the crossroads of metastasis and immunity. Sci. Immunol. 6, eabg3551 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Rodriguez, A. B. & Engelhard, V. H. Insights into tumor-associated tertiary lymphoid structures: novel targets for antitumor immunity and cancer immunotherapy. Cancer Immunol. Res. 8, 1338–1345 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhou, L., Xu, B., Liu, Y. & Wang, Z. Tertiary lymphoid structure signatures are associated with survival and immunotherapy response in muscle-invasive bladder cancer. Oncoimmunology 10, 1915574 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Meylan, M. et al. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. Immunity 55, 527–541.e5 (2022).

    Article  CAS  PubMed  Google Scholar 

  82. Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Thommen, D. S. et al. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat. Med. 24, 994–1004 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Workel, H. H. et al. A transcriptionally distinct CXCL13+CD103+CD8+ T-cell population is associated with B-cell recruitment and neoantigen load in human cancer. Cancer Immunol. Res. 7, 784–796 (2019).

    Article  CAS  PubMed  Google Scholar 

  85. Rodriguez, A. B. et al. Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts. Cell Rep. 36, 109422 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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 

  87. Kharchenko, P. V., Silberstein, L. & Scadden, D. T. Bayesian approach to single-cell differential expression analysis. Nat. Methods 11, 740–742 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sakimura, C. et al. B cells in tertiary lymphoid structures are associated with favorable prognosis in gastric cancer. J. Surg. Res. 215, 74–82 (2017).

    Article  CAS  PubMed  Google Scholar 

  89. 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 

  90. Cheng, H. W. et al. CCL19-producing fibroblastic stromal cells restrain lung carcinoma growth by promoting local antitumor T-cell responses. J. Allergy Clin. Immunol. 142, 1257–1271.e4 (2018).

    Article  CAS  PubMed  Google Scholar 

  91. Yan, Y. et al. CCL19 and CCR7 expression, signaling pathways, and adjuvant functions in viral infection and prevention. Front. Cell Dev. Biol. 7, 212 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Molodtsov, A. K. et al. Resident memory CD8+ T cells in regional lymph nodes mediate immunity to metastatic melanoma. Immunity 54, 2117–2132.e7 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Van Krimpen, A. et al. Immune suppression in the tumor-draining lymph node corresponds with distant disease recurrence in patients with melanoma. Cancer Cell 40, 798–799 (2022).

    Article  PubMed  Google Scholar 

  94. Giuliano, A. E. et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: the ACOSOG Z0011 (Alliance) randomized clinical trial. J. Am. Med. Assoc. 318, 918–926 (2017).

    Article  Google Scholar 

  95. Faries, M. B. et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N. Engl. J. Med. 376, 2211–2222 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Li, Y. L. et al. Single-cell analysis reveals immune modulation and metabolic switch in tumor-draining lymph nodes. Oncoimmunology 9, 1830513 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  97. 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 

  98. Riedel, A., Shorthouse, D., Haas, L., Hall, B. A. & Shields, J. Tumor-induced stromal reprogramming drives lymph node transformation. Nat. Immunol. 17, 1118–1127 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Nicolas, A. M. et al. Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer. Cancer Cell 40, 168–184.e13 (2022).

    Article  CAS  PubMed  Google Scholar 

  100. Chen, Y., McAndrews, K. M. & Kalluri, R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat. Rev. Clin. Oncol. 18, 792–804 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ono, S. et al. Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotype. Chest 143, 963–970 (2013).

    Article  PubMed  Google Scholar 

  102. Ito, M. et al. Prognostic impact of cancer-associated stromal cells in patients with stage I lung adenocarcinoma. Chest 142, 151–158 (2012).

    Article  PubMed  Google Scholar 

  103. Liao, Y., Ni, Y., He, R., Liu, W. & Du, J. Clinical implications of fibroblast activation protein-α in non-small cell lung cancer after curative resection: a new predictor for prognosis. J. Cancer Res. Clin. Oncol. 139, 1523–1528 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Paulsson, J. et al. Prognostic significance of stromal platelet-derived growth factor β-receptor expression in human breast cancer. Am. J. Pathol. 175, 334–341 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Wang, Z. et al. Cancer-associated fibroblasts suppress cancer development: the other side of the coin. Front. Cell Dev. Biol. 9, 613534 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  106. McAndrews, K. M. et al. Identification of functional heterogeneity of carcinoma-associated fibroblasts with distinct IL6-mediated therapy resistance in pancreatic cancer. Cancer Discov. 12, 1580–1597 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ganguly, D. et al. Cancer-associated fibroblasts: versatile players in the tumor microenvironment. Cancers (Basel) 12, 2652 (2020).

    Article  CAS  PubMed  Google Scholar 

  108. Wang, Y. et al. Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response. Cell Discov. 7, 36 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zimmermann, T. et al. Isolation and characterization of rheumatoid arthritis synovial fibroblasts from primary culture — primary culture cells markedly differ from fourth-passage cells. Arthritis Res. 3, 72–76 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Pinchuk, I. V. et al. Human colonic myofibroblasts promote expansion of CD4+CD25highFoxp3+ regulatory T cells. Gastroenterology 140, 2019–2030 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Carmona-Rivera, C. et al. Synovial fibroblast–neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci. Immunol. 2, eaag3358 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Huang, H. et al. Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. Cancer Cell 40, 656–673.e7 (2022).

    Article  CAS  PubMed  Google Scholar 

  114. Xing, X. et al. Decoding the multicellular ecosystem of lung adenocarcinoma manifested as pulmonary subsolid nodules by single-cell RNA sequencing. Sci. Adv. 7, eabd9738 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Su, H., Na, N., Zhang, X. & Zhao, Y. The biological function and significance of CD74 in immune diseases. Inflamm. Res. 66, 209–216 (2017).

    Article  CAS  PubMed  Google Scholar 

  116. Kishimoto, T. & Kang, S. IL-6 revisited: from rheumatoid arthritis to CAR T cell therapy and COVID-19. Annu. Rev. Immunol. 40, 323–348 (2022).

    Article  PubMed  Google Scholar 

  117. Hill, C. et al. Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis. Cell Death Dis. 10, 591 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  118. 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  Google Scholar 

  119. Harryvan, T. J. et al. Enhanced antigen cross-presentation in human colorectal cancer-associated fibroblasts through upregulation of the lysosomal protease cathepsin S. J. Immunother. Cancer 10, e003591 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Dubey, C., Croft, M. & Swain, S. L. Naive and effector CD4 T cells differ in their requirements for T cell receptor versus costimulatory signals. J. Immunol. 157, 3280–3289 (1996).

    Article  CAS  PubMed  Google Scholar 

  122. Jerby-Arnon, L. & Regev, A. DIALOGUE maps multicellular programs in tissue from single-cell or spatial transcriptomics data. Nat. Biotechnol. 40, 1467–1477 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Toulmin, S. A. et al. Type II alveolar cell MHCII improves respiratory viral disease outcomes while exhibiting limited antigen presentation. Nat. Commun. 12, 3993 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Chinen, T. et al. An essential role for the IL-2 receptor in Treg cell function. Nat. Immunol. 17, 1322–1333 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hassan, R. et al. Mesothelin immunotherapy for cancer: ready for prime time? J. Clin. Oncol. 34, 4171–4179 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Ruhland, M. K. et al. Visualizing synaptic transfer of tumor antigens among dendritic cells. Cancer Cell 37, 786–799.e5 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Zander, R. et al. CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer. Immunity 51, 1028–1042 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ahrends, T. et al. CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities. Nat. Commun. 10, 5531 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Sledzinska, A. et al. Regulatory T cells restrain interleukin-2- and Blimp-1-dependent acquisition of cytotoxic function by CD4+ T cells. Immunity 52, 151–166.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Binnewies, M. et al. Unleashing type-2 dendritic cells to drive protective antitumor CD4+ T cell immunity. Cell 177, 556–571.e16 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Oh, D. Y. & Fong, L. Cytotoxic CD4+ T cells in cancer: expanding the immune effector toolbox. Immunity 54, 2701–2711 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Johnson, D. B. et al. Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat. Commun. 7, 10582 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Rodig, S. J. et al. MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci. Transl. Med. 10, eaar3342 (2018).

    Article  PubMed  Google Scholar 

  134. Oliveira, G. et al. Landscape of helper and regulatory antitumour CD4+ T cells in melanoma. Nature 605, 532–538 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Joshi, K. et al. Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer. Nat. Med. 25, 1549–1559 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Alspach, E. et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 574, 696–701 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Dammeijer, F. et al. The PD-1/PD-L1-checkpoint restrains T cell immunity in tumor-draining lymph nodes. Cancer Cell 38, 685–700.e8 (2020).

    Article  CAS  PubMed  Google Scholar 

  139. Oh, S. A. et al. PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer. Nat. Cancer 1, 681–691 (2020).

    Article  CAS  PubMed  Google Scholar 

  140. Mattiuz, R. et al. Type 1 conventional dendritic cells and interferons are required for spontaneous CD4+ and CD8+ T-cell protective responses to breast cancer. Clin. Transl. Immunol. 10, e1305 (2021).

    Article  CAS  Google Scholar 

  141. Corse, E., Gottschalk, R. A. & Allison, J. P. Strength of TCR-peptide/MHC interactions and in vivo T cell responses. J. Immunol. 186, 5039–5045 (2011).

    Article  CAS  PubMed  Google Scholar 

  142. Van Panhuys, N. TCR signal strength alters T–DC activation and interaction times and directs the outcome of differentiation. Front. Immunol. 7, 6 (2016).

    PubMed  PubMed Central  Google Scholar 

  143. Daniel, B. et al. Divergent clonal differentiation trajectories of T cell exhaustion. Nat. Immunol. 23, 1614–1627 (2022).

    Article  CAS  PubMed  Google Scholar 

  144. Shakiba, M. et al. TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion. J. Exp. Med. 219, e20201966 (2022).

    Article  CAS  PubMed  Google Scholar 

  145. Tran, M. A. & Bhardwaj, N. Exhausted T cell phenotypes depend on TCR signal strength. Nat. Rev. Immunol. 22, 206 (2022).

    Article  CAS  PubMed  Google Scholar 

  146. Malandro, N. et al. Clonal abundance of tumor-specific CD4+ T cells potentiates efficacy and alters susceptibility to exhaustion. Immunity 44, 179–193 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Miggelbrink, A. M. et al. CD4 T-cell exhaustion: does it exist and what are its roles in cancer? Clin. Cancer Res. 27, 5742–5752 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. McLachlan, J. B. & Jenkins, M. K. Migration and accumulation of effector CD4+ T cells in nonlymphoid tissues. Proc. Am. Thorac. Soc. 4, 439–442 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kong, W. et al. Capybara: a computational tool to measure cell identity and fate transitions. Cell Stem Cell 29, 635–649.e11 (2022).

    Article  CAS  PubMed  Google Scholar 

  150. Azharuddin, M. et al. Nano toolbox in immune modulation and nanovaccines. Trends Biotechnol. 40, 1195–1212 (2022).

    Article  CAS  PubMed  Google Scholar 

  151. Aikins, M. E., Xu, C. & Moon, J. J. Engineered nanoparticles for cancer vaccination and immunotherapy. Acc. Chem. Res. 53, 2094–2105 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Saito, R., Kobayashi, T., Kashima, S., Matsumoto, K. & Ogawa, O. Faithful preclinical mouse models for better translation to bedside in the field of immuno-oncology. Int. J. Clin. Oncol. 25, 831–841 (2020).

    Article  PubMed  Google Scholar 

  153. Cupovic, J. et al. Adenovirus vector vaccination reprograms pulmonary fibroblastic niches to support protective inflating memory CD8+ T cells. Nat. Immunol. 22, 1042–1051 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  156. 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).

    Article  PubMed  Google Scholar 

  157. Lavie, D., Ben-Shmuel, A., Erez, N. & Scherz-Shouval, R. Cancer-associated fibroblasts in the single-cell era. Nat. Cancer 3, 793–807 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author thanks I. Angelidis for his contributions in figure preparations.

Author information

Authors and Affiliations

  1. Institute of Bioinnovation, Biomedical Sciences Research Center ‘Alexander Fleming’, Vari, Greece

    Maria Tsoumakidou

Authors
  1. Maria Tsoumakidou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The author handled all aspects of the article.

Corresponding author

Correspondence to Maria Tsoumakidou.

Ethics declarations

Competing interests

The author declares no competing interests.

Peer review

Peer review information

Nature Reviews Cancer thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

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

Glossary

Affinity maturation

A process whereby hypermutated B cell receptors (BCRs) undergo positive selection depending on their affinity for antigens that are retained on follicular dendritic cells (FDCs) in the form of immune complexes.

B cell and T cell lymphopoiesis

A sequence of events of haematopoietic stem cell differentiation to mature B cells and T cells that express functional B cell receptors (BCRs) and T cell receptors (TCRs).

Bone marrow mesenchymal stem cells

(BM-MSCs). As final remnants of the embryonic mesenchyme, these are self-renewable pluripotent cells found mainly in the umbilical cord, the bone marrow and the fat, and are key to tissue repair and regeneration.

Central tolerance

A process that takes place in the bone marrow and the thymus, eliminating any developing B lymphocytes or T lymphocytes, respectively, that are reactive to self.

Conduit networks

Tubular re-entrant loop networks consisting of a core of organized collagen fibrils ensheathed by T cell-zone reticular cells (TRCs), through which lymph fluid travels and from which dendritic cells capture antigens.

Cross-presentation

The ability of mainly professional antigen-presenting cells (APCs) to process and present extracellular antigens in the context of major histocompatibility complex (MHC) class I rather than MHC class II, leading to CD8+ T cell activation.

Lymphoid follicles

Unstructured B cell and T cell aggregates or highly organized aggregates with distinct B cell and T cell areas; that is, primary lymphoid follicles without and secondary with germinal centres for plasma cell formation, high endothelial venules and lymphatic vessels for lymphocyte and antigen trafficking, found in homeostatic gut tissue and several chronically inflamed tissues.

Lymphoid tissue organizer cells

(LTos). Mesenchymal lymphoid tissue cells that express the lymphotoxin-β receptor (LTβR) and determine the location and drive the initial steps of lymph node formation.

Lymphotoxin

A member of the tumour necrosis factor (TNF) superfamily of cytokines that is critical for the development of secondary lymphoid organs (SLOs) and tertiary lymphoid organs (TLOs).

Major histocompatibility complex

(MHC). A cell surface peptide-binding protein which selects sequences of amino acids for antigen presentation to CD8+ T cells (MHC class I) or CD4+ T cells (MHC class II) that are expressed by all nucleated cells of the body (MHC class I) or selectively by professional or amateur antigen-presenting cells (APCs) (MHC class II).

Mesenchyme

A type of embryonic tissue that mainly comes from the mesoderm, consists of loose stellate-shaped undifferentiated cells embedded in the extracellular matrix (ECM) and gives rise to all connective tissues.

Secondary lymphoid organs

(SLOs). Sites where adaptive immune responses are generated and where B lymphocytes and T lymphocytes are maintained, including the spleen, lymph nodes and mucosa-associated lymphoid tissues.

Tertiary lymphoid organs

(TLOs). Ectopic lymphoid follicles induced in peripheral tissues under conditions of prolonged inflammation, such as autoimmunity, non-resolving infections and cancer. They may show distinct B cell and T cell areas and host germinal centre reactions (primary versus secondary lymphoid follicles).

Trajectory inference analysis

A computational approach used in single-cell RNA sequencing (scRNA-seq) to construct a pathway of how cells traverse though different states over time.

Tumour mesenchyme

Vastly heterogeneous non-epithelial, non-endothelial, non-leukocyte elongated cells lacking mutations found in cancer cells.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsoumakidou, M. The advent of immune stimulating CAFs in cancer. Nat Rev Cancer 23, 258–269 (2023). https://doi.org/10.1038/s41568-023-00549-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-023-00549-7

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