Immunological hallmarks of stromal cells in the tumour microenvironment

Key Points

  • Non-haematopoietic stromal cells in the tumour microenvironment actively interact with infiltrating leukocytes. Emerging evidence also suggests that the stromal compartment can shape antitumour immunity and responsiveness to immunotherapy.

  • Dysfunctional endothelial cells and aberrant pericyte coverage in tumour blood vessels results in tortuous and leaky vessels, which greatly impinge on leukocyte infiltration. Diapedesis of effector immune cells is further limited by the reduced expression of endothelial adhesive molecules.

  • Fibroblasts contribute to shaping the immune cell populations in tumours by secreting chemokines that can selectively repel effector T cells while favouring the recruitment of immunosuppressive cells.

  • Stromal cells in the tumour microenvironment can also actively hinder antitumour immunity by several mechanisms, including expression of inhibitory receptors, production of molecules that induce T cell apoptosis and secretion of immunosuppressive factors.

  • Overcoming immune suppression is of the upmost importance for cancer treatment. In light of the increasing evidence that suggests a role for the tumour stroma in limiting antitumour immune responses, we anticipate that therapies targeting stromal cells in the tumour microenvironment will be likely to provide enormous benefits.

Abstract

A dynamic and mutualistic interaction between tumour cells and the surrounding stroma promotes the initiation, progression, metastasis and chemoresistance of solid tumours. Far less understood is the relationship between the stroma and tumour-infiltrating leukocytes; however, emerging evidence suggests that the stromal compartment can shape antitumour immunity and responsiveness to immunotherapy. Thus, there is growing interest in elucidating the immunomodulatory roles of the stroma that evolve within the tumour microenvironment. In this Review, we discuss the evidence that stromal determinants interact with leukocytes and influence antitumour immunity, with emphasis on the immunological attributes of stromal cells that may foster their protumorigenic function.

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Figure 1: Cellular and architectural changes in the tumour microenvironment.
Figure 2: Regulation of immune cell infiltration into the tumour microenvironment.
Figure 3: Stromal cell–immune cell crosstalk in the tumour microenvironment.

References

  1. 1

    Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009).

    CAS  Google Scholar 

  2. 2

    Polyak, K., Haviv, I. & Campbell, I. G. Co-evolution of tumor cells and their microenvironment. Trends Genet. 25, 30–38 (2009). References 1 and 2 are comprehensive reviews on the development and function of the TME.

    CAS  Google Scholar 

  3. 3

    Nakasone, E. S. et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21, 488–503 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013). This study is a seminal review on the current state of tumour immunotherapies in the clinic.

    Google Scholar 

  5. 5

    Pivarcsi, A. et al. Tumor immune escape by the loss of homeostatic chemokine expression. Proc. Natl Acad. Sci. USA 104, 19055–19060 (2007).

    CAS  PubMed  Google Scholar 

  6. 6

    Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).

    CAS  Google Scholar 

  7. 7

    Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Castermans, K. & Griffioen, A. W. Tumor blood vessels, a difficult hurdle for infiltrating leukocytes. Biochim. Biophys. Acta 1776, 160–174 (2007).

    CAS  Google Scholar 

  10. 10

    Nagy, J. A., Dvorak, A. M. & Dvorak, H. F. VEGF-A and the induction of pathological angiogenesis. Annu. Rev. Pathol. 2, 251–275 (2007).

    CAS  PubMed  Google Scholar 

  11. 11

    Jain, R. K. Molecular regulation of vessel maturation. Nat. Med. 9, 685–693 (2003).

    CAS  PubMed  Google Scholar 

  12. 12

    Greenberg, J. I. et al. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456, 809–813 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Furuya, M. et al. Expression of regulator of G protein signalling protein 5 (RGS5) in the tumour vasculature of human renal cell carcinoma. J. Pathol. 203, 551–558 (2004).

    CAS  PubMed  Google Scholar 

  14. 14

    Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Goel, S. et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev. 91, 1071–1121 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Griffioen, A. W., Damen, C. A., Blijham, G. H. & Groenewegen, G. Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood 88, 667–673 (1996).

    CAS  PubMed  Google Scholar 

  17. 17

    Griffioen, A. W., Damen, C. A., Martinotti, S., Blijham, G. H. & Groenewegen, G. Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res. 56, 1111–1117 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Bouzin, C., Brouet, A., De Vriese, J., Dewever, J. & Feron, O. Effects of vascular endothelial growth factor on the lymphocyte–endothelium interactions: identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy. J. Immunol. 178, 1505–1511 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Buckanovich, R. J. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat. Med. 14, 28–36 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Delfortrie, S. et al. Egfl7 promotes tumor escape from immunity by repressing endothelial cell activation. Cancer Res. 71, 7176–7186 (2011).

    CAS  PubMed  Google Scholar 

  21. 21

    Shetty, S. et al. Common lymphatic endothelial and vascular endothelial receptor-1 mediates the transmigration of regulatory T cells across human hepatic sinusoidal endothelium. J. Immunol. 186, 4147–4155 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Nummer, D. et al. Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma. J. Natl Cancer Inst. 99, 1188–1199 (2007).

    CAS  PubMed  Google Scholar 

  23. 23

    Schenkel, A. R., Mamdouh, Z., Chen, X., Liebman, R. M. & Muller, W. A. CD99 plays a major role in the migration of monocytes through endothelial junctions. Nat. Immunol. 3, 143–150 (2002).

    CAS  PubMed  Google Scholar 

  24. 24

    Talmadge, J. E. & Gabrilovich, D. I. History of myeloid-derived suppressor cells. Nat. Rev. Cancer 13, 739–752 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Loeffler, M., Kruger, 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). One of the first studies demonstrating that targeting CAFs affects tumour progression.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Liao, D., Luo, Y., Markowitz, D., Xiang, R. & Reisfeld, R. A. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS ONE 4, e7965 (2009). This study details the use of a FAP-targeted vaccine to deplete CAFs.

    PubMed  PubMed Central  Google Scholar 

  27. 27

    Murdoch, C., Giannoudis, A. & Lewis, C. E. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104, 2224–2234 (2004).

    CAS  Google Scholar 

  28. 28

    Tan, W. et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling. Nature 470, 548–553 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    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). This study provides an example of how blocking immunosuppressive products from CAFs can impair tumour growth in an immune-mediated manner.

    CAS  Google Scholar 

  30. 30

    Ammirante, M., Shalapour, S., Kang, Y., Jamieson, C. A. & Karin, M. Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc. Natl Acad. Sci. USA 111, 14776–14781 (2014). This study provides an example of a feedback loop between hypoxia, CAFs and B cells promoting tumour progression.

    CAS  PubMed  Google Scholar 

  31. 31

    Shalapour, S. et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521, 94–98 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

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

    CAS  Google Scholar 

  33. 33

    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). This study is an important example of how the ECM in the TME affects T cell localization and motility in human tumours.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).

    CAS  PubMed  Google Scholar 

  36. 36

    Caruana, I. et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat. Med. 21, 524–529 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014). References 37 and 38 are recent examples of how targeting FAP+ cells may have negative effects for the host.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Valujskikh, A., Lantz, O., Celli, S., Matzinger, P. & Heeger, P. S. Cross-primed CD8+ T cells mediate graft rejection via a distinct effector pathway. Nat. Immunol. 3, 844–851 (2002).

    CAS  PubMed  Google Scholar 

  40. 40

    Savinov, A. Y., Wong, F. S., Stonebraker, A. C. & Chervonsky, A. V. Presentation of antigen by endothelial cells and chemoattraction are required for homing of insulin-specific CD8+ T cells. J. Exp. Med. 197, 643–656 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Zang, X. et al. Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas. Mod. Pathol. 23, 1104–1112 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Rodig, N. et al. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur. J. Immunol. 33, 3117–3126 (2003).

    CAS  PubMed  Google Scholar 

  43. 43

    Mazanet, M. M. & Hughes, C. C. B7-H1 is expressed by human endothelial cells and suppresses T cell cytokine synthesis. J. Immunol. 169, 3581–3588 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Huang, X. et al. Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion. J. Exp. Med. 207, 505–520 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Seaman, S. et al. Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 11, 539–554 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Ma, L. et al. Ig gene-like molecule CD31 plays a nonredundant role in the regulation of T-cell immunity and tolerance. Proc. Natl Acad. Sci. USA 107, 19461–19466 (2010).

    CAS  PubMed  Google Scholar 

  47. 47

    Secchiero, P. & Zauli, G. The puzzling role of TRAIL in endothelial cell biology. Arterioscler. Thromb. Vasc. Biol. 28, e4, author reply e5–e6 (2008).

    CAS  PubMed  Google Scholar 

  48. 48

    Motz, G. T. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014). This study provides an example of how the tumour endothelium can contribute to immunosuppression by promoting T cell apoptosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Mulligan, J. K., Day, T. A., Gillespie, M. B., Rosenzweig, S. A. & Young, M. R. Secretion of vascular endothelial growth factor by oral squamous cell carcinoma cells skews endothelial cells to suppress T-cell functions. Hum. Immunol. 70, 375–382 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Mulligan, J. K. & Young, M. R. Tumors induce the formation of suppressor endothelial cells in vivo. Cancer Immunol. Immunother. 59, 267–277 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Casos, K. et al. Tumor cells induce COX-2 and mPGES-1 expression in microvascular endothelial cells mainly by means of IL-1 receptor activation. Microvasc. Res. 81, 261–268 (2011).

    CAS  PubMed  Google Scholar 

  52. 52

    Munn, D. H. & Mellor, A. L. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest. 117, 1147–1154 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Pilotte, L. et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl Acad. Sci. USA 109, 2497–2502 (2012).

    CAS  Google Scholar 

  54. 54

    Lund, A. W. et al. VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. Cell Rep. 1, 191–199 (2012). This study details how LECs can promote a tolerizing environment in the tumour and contribute to overall immunosuppression.

    CAS  PubMed  Google Scholar 

  55. 55

    Cohen, J. N. et al. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J. Exp. Med. 207, 681–688 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Tamburini, B. A., Burchill, M. A. & Kedl, R. M. Antigen capture and archiving by lymphatic endothelial cells following vaccination or viral infection. Nat. Commun. 5, 3989 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Swartz, M. A. & Lund, A. W. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat. Rev. Cancer 12, 210–219 (2012). This review details the current state of the field of tumour lymphatics and mechanobiology.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Ng, C. P., Hinz, B. & Swartz, M. A. Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J. Cell Sci. 118, 4731–4739 (2005).

    CAS  PubMed  Google Scholar 

  59. 59

    Wipff, P. J., Rifkin, D. B., Meister, J. J. & Hinz, B. Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J. Cell Biol. 179, 1311–1323 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Ahamed, J. et al. In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1. Blood 112, 3650–3660 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Tiegs, G. & Lohse, A. W. Immune tolerance: what is unique about the liver. J. Autoimmun. 34, 1–6 (2010).

    CAS  PubMed  Google Scholar 

  62. 62

    Ichikawa, S., Mucida, D., Tyznik, A. J., Kronenberg, M. & Cheroutre, H. Hepatic stellate cells function as regulatory bystanders. J. Immunol. 186, 5549–5555 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Schildberg, F. A. et al. Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism. Hepatology 54, 262–272 (2011).

    CAS  PubMed  Google Scholar 

  64. 64

    Zhao, W. et al. Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice. Int. J. Cancer 129, 2651–2661 (2011).

    CAS  PubMed  Google Scholar 

  65. 65

    Zhao, W. et al. Hepatic stellate cells promote tumor progression by enhancement of immunosuppressive cells in an orthotopic liver tumor mouse model. Lab. Invest. 94, 182–191 (2014).

    CAS  PubMed  Google Scholar 

  66. 66

    Olson, L. E. & Soriano, P. PDGFRβ signaling regulates mural cell plasticity and inhibits fat development. Dev. Cell 20, 815–826 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Ochs, K. et al. Immature mesenchymal stem cell-like pericytes as mediators of immunosuppression in human malignant glioma. J. Neuroimmunol. 265, 106–116 (2013).

    CAS  PubMed  Google Scholar 

  68. 68

    Bose, A. et al. Tumor-derived vascular pericytes anergize Th cells. J. Immunol. 191, 971–981 (2013).

    CAS  PubMed  Google Scholar 

  69. 69

    Dulauroy, S., Di Carlo, S. E., Langa, F., Eberl, G. & Peduto, L. Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat. Med. 18, 1262–1270 (2012).

    CAS  PubMed  Google Scholar 

  70. 70

    Djouad, F. et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 102, 3837–3844 (2003).

    CAS  PubMed  Google Scholar 

  71. 71

    Montesinos, J. J. et al. In vitro evidence of the presence of mesenchymal stromal cells in cervical cancer and their role in protecting cancer cells from cytotoxic T cell activity. Stem Cells Dev. 22, 2508–2519 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Han, Z. et al. Immunosuppressive effect of bone marrow-derived mesenchymal stem cells in inflammatory microenvironment favours the growth of B16 melanoma cells. J. Cell. Mol. Med. 15, 2343–2352 (2011). This study provides an example of how MSCs function to promote immunosuppression and tumour progression.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Gnecchi, M., Zhang, Z., Ni, A. & Dzau, V. J. Paracrine mechanisms in adult stem cell signaling and therapy. Circ. Res. 103, 1204–1219 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Saunier, E. F. & Akhurst, R. J. TGF β inhibition for cancer therapy. Curr. Cancer Drug Targets 6, 565–578 (2006).

    CAS  PubMed  Google Scholar 

  75. 75

    Ahmadzadeh, M. & Rosenberg, S. A. TGF-β 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J. Immunol. 174, 5215–5223 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Broderick, L. & Bankert, R. B. Membrane-associated TGF-β1 inhibits human memory T cell signaling in malignant and nonmalignant inflammatory microenvironments. J. Immunol. 177, 3082–3088 (2006).

    CAS  PubMed  Google Scholar 

  77. 77

    Byrne, S. N., Knox, M. C. & Halliday, G. M. TGFβ is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction. Immunol. Cell Biol. 86, 92–97 (2008).

    CAS  PubMed  Google Scholar 

  78. 78

    Balsamo, M. et al. Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc. Natl Acad. Sci. USA 106, 20847–20852 (2009).

    CAS  PubMed  Google Scholar 

  79. 79

    Li, T. et al. Colorectal carcinoma-derived fibroblasts modulate natural killer cell phenotype and antitumor cytotoxicity. Med. Oncol. 30, 663 (2013).

    PubMed  Google Scholar 

  80. 80

    De Monte, L. et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J. Exp. Med. 208, 469–478 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Paunescu, V. et al. Tumour-associated fibroblasts and mesenchymal stem cells: more similarities than differences. J. Cell. Mol. Med. 15, 635–646 (2011).

    CAS  PubMed  Google Scholar 

  82. 82

    Kim, J. H. et al. The role of myofibroblasts in upregulation of S100A8 and S100A9 and the differentiation of myeloid cells in the colorectal cancer microenvironment. Biochem. Biophys. Res. Commun. 423, 60–66 (2012).

    CAS  PubMed  Google Scholar 

  83. 83

    Menetrier-Caux, C. et al. Inhibition of the differentiation of dendritic cells from CD34+ progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood 92, 4778–4791 (1998).

    CAS  PubMed  Google Scholar 

  84. 84

    Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. Science 330, 827–830 (2010).

    CAS  PubMed  Google Scholar 

  85. 85

    Wang, L. C. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Hauzenberger, D., Olivier, P., Gundersen, D. & Ruegg, C. Tenascin-C inhibits β integrin-dependent T lymphocyte adhesion to fibronectin through the binding of its fnIII 1–5 repeats to fibronectin. Eur. J. Immunol. 29, 1435–1447 (1999).

    CAS  PubMed  Google Scholar 

  87. 87

    Ruegg, C. R., Chiquet-Ehrismann, R. & Alkan, S. S. Tenascin, an extracellular matrix protein, exerts immunomodulatory activities. Proc. Natl Acad. Sci. USA 86, 7437–7441 (1989).

    CAS  PubMed  Google Scholar 

  88. 88

    Armant, M. et al. CD47 ligation selectively downregulates human interleukin 12 production. J. Exp. Med. 190, 1175–1182 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Demeure, C. E. et al. CD47 engagement inhibits cytokine production and maturation of human dendritic cells. J. Immunol. 164, 2193–2199 (2000).

    CAS  PubMed  Google Scholar 

  90. 90

    Reinhold, M. I., Lindberg, F. P., Kersh, G. J., Allen, P. M. & Brown, E. J. Costimulation of T cell activation by integrin-associated protein (CD47) is an adhesion-dependent, CD28-independent signaling pathway. J. Exp. Med. 185, 1–11 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Vallejo, A. N., Mugge, L. O., Klimiuk, P. A., Weyand, C. M. & Goronzy, J. J. Central role of thrombospondin-1 in the activation and clonal expansion of inflammatory T cells. J. Immunol. 164, 2947–2954 (2000).

    CAS  PubMed  Google Scholar 

  92. 92

    Avice, M. N., Rubio, M., Sergerie, M., Delespesse, G. & Sarfati, M. Role of CD47 in the induction of human naive T cell anergy. J. Immunol. 167, 2459–2468 (2001).

    CAS  PubMed  Google Scholar 

  93. 93

    Li, Z. et al. Interactions of thrombospondins with α4β1 integrin and CD47 differentially modulate T cell behavior. J. Cell Biol. 157, 509–519 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Parks, W. C., Wilson, C. L. & Lopez-Boado, Y. S. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 4, 617–629 (2004).

    CAS  PubMed  Google Scholar 

  95. 95

    Coussens, L. M., Zitvogel, L. & Palucka, A. K. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339, 286–291 (2013). This comprehensive review details the contributions of multiple immune cells to inflammation in the TME and provides examples of new targets.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Leek, R. D. et al. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 56, 4625–4629 (1996).

    CAS  Google Scholar 

  97. 97

    Onita, T. et al. Hypoxia-induced, perinecrotic expression of endothelial Per–ARNT–Sim domain protein-1/hypoxia-inducible factor-2α correlates with tumor progression, vascularization, and focal macrophage infiltration in bladder cancer. Clin. Cancer Res. 8, 471–480 (2002).

    CAS  PubMed  Google Scholar 

  98. 98

    Takanami, I., Takeuchi, K. & Kodaira, S. Tumor-associated macrophage infiltration in pulmonary adenocarcinoma: association with angiogenesis and poor prognosis. Oncology 57, 138–142 (1999).

    CAS  PubMed  Google Scholar 

  99. 99

    Lin, E. Y. et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66, 11238–11246 (2006).

    CAS  Google Scholar 

  100. 100

    Nozawa, H., Chiu, C. & Hanahan, D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc. Natl Acad. Sci. USA 103, 12493–12498 (2006).

    CAS  Google Scholar 

  101. 101

    Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737–744 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Shojaei, F. et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450, 825–831 (2007).

    CAS  Google Scholar 

  103. 103

    Yang, L. et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6, 409–421 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Coussens, L. M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Soucek, L. et al. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat. Med. 13, 1211–1218 (2007).

    CAS  Google Scholar 

  106. 106

    Starkey, J. R., Crowle, P. K. & Taubenberger, S. Mast-cell-deficient W/Wv mice exhibit a decreased rate of tumor angiogenesis. Int. J. Cancer 42, 48–52 (1988).

    CAS  PubMed  Google Scholar 

  107. 107

    Munitz, A. & Levi-Schaffer, F. Eosinophils: 'new' roles for 'old' cells. Allergy 59, 268–275 (2004).

    CAS  PubMed  Google Scholar 

  108. 108

    Zumsteg, A. & Christofori, G. Myeloid cells and lymphangiogenesis. Cold Spring Harb. Perspect. Med. 2, a006494 (2012).

    PubMed  PubMed Central  Google Scholar 

  109. 109

    Balkwill, F., Charles, K. A. & Mantovani, A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7, 211–217 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Lu, P., Takai, K., Weaver, V. M. & Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 3, a005058 (2011).

    PubMed  PubMed Central  Google Scholar 

  111. 111

    Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014). This review details the pleiotropic functions of macrophages in the TME.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Terabe, M., Park, J. M. & Berzofsky, J. A. Role of IL-13 in regulation of anti-tumor immunity and tumor growth. Cancer Immunol. Immunother. 53, 79–85 (2004).

    CAS  PubMed  Google Scholar 

  114. 114

    Ammirante, M., Luo, J. L., Grivennikov, S., Nedospasov, S. & Karin, M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464, 302–305 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Gommerman, J. L. & Browning, J. L. Lymphotoxin/LIGHT, lymphoid microenvironments and autoimmune disease. Nat. Rev. Immunol. 3, 642–655 (2003).

    CAS  PubMed  Google Scholar 

  116. 116

    Textor, A. et al. Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNγ. Cancer Res. 74, 6796–6805 (2014).

    CAS  PubMed  Google Scholar 

  117. 117

    Achen, M. G., McColl, B. K. & Stacker, S. A. Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 7, 121–127 (2005).

    CAS  PubMed  Google Scholar 

  118. 118

    Adotevi, O. et al. A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J. Immunother. 33, 991–998 (2010). This study provides an example of how reducing the increased vascularization in tumours can modulate the immune landscape and reduce tumour metastasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Ko, J. S. et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin. Cancer Res. 15, 2148–2157 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Mueller, M. M. & Fusenig, N. E. Friends or foes — bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).

    CAS  Google Scholar 

  121. 121

    Sugimoto, H., Mundel, T. M., Kieran, M. W. & Kalluri, R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol. Ther. 5, 1640–1646 (2006).

    CAS  PubMed  Google Scholar 

  122. 122

    Henry, L. R. et al. Clinical implications of fibroblast activation protein in patients with colon cancer. Clin. Cancer Res. 13, 1736–1741 (2007).

    CAS  PubMed  Google Scholar 

  123. 123

    Tsujino, T. et al. Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin. Cancer Res. 13, 2082–2090 (2007).

    CAS  PubMed  Google Scholar 

  124. 124

    Abramsson, A., Lindblom, P. & Betsholtz, C. Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J. Clin. Invest. 112, 1142–1151 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Gerhardt, H. & Betsholtz, C. Endothelial–pericyte interactions in angiogenesis. Cell Tissue Res. 314, 15–23 (2003).

    PubMed  Google Scholar 

  126. 126

    Maciag, P. C., Seavey, M. M., Pan, Z. K., Ferrone, S. & Paterson, Y. Cancer immunotherapy targeting the high molecular weight melanoma-associated antigen protein results in a broad antitumor response and reduction of pericytes in the tumor vasculature. Cancer Res. 68, 8066–8075 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Lund, A. W. & Swartz, M. A. Role of lymphatic vessels in tumor immunity: passive conduits or active participants? J. Mammary Gland Biol. Neoplasia 15, 341–352 (2010).

    PubMed  Google Scholar 

  128. 128

    Feig, C. et al. The pancreas cancer microenvironment. Clin. Cancer Res. 18, 4266–4276 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Bhowmick, N. A., Neilson, E. G. & Moses, H. L. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Strnad, H. et al. Head and neck squamous cancer stromal fibroblasts produce growth factors influencing phenotype of normal human keratinocytes. Histochem. Cell Biol. 133, 201–211 (2010).

    CAS  PubMed  Google Scholar 

  131. 131

    LeBedis, C., Chen, K., Fallavollita, L., Boutros, T. & Brodt, P. Peripheral lymph node stromal cells can promote growth and tumorigenicity of breast carcinoma cells through the release of IGF-I and EGF. Int. J. Cancer 100, 2–8 (2002).

    CAS  PubMed  Google Scholar 

  132. 132

    Levental, K. R. et al.Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Shields, J. D. et al. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11, 526–538 (2007).

    CAS  PubMed  Google Scholar 

  134. 134

    Chauhan, V. P. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 2516 (2013).

    PubMed  PubMed Central  Google Scholar 

  135. 135

    Peranzoni, E., Rivas-Caicedo, A., Bougherara, H., Salmon, H. & Donnadieu, E. Positive and negative influence of the matrix architecture on antitumor immune surveillance. Cell. Mol. Life Sci. 70, 4431–4448 (2013).

    CAS  PubMed  Google Scholar 

  136. 136

    Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Steg, A. D. et al. Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin. Cancer Res. 18, 869–881 (2012).

    CAS  PubMed  Google Scholar 

  138. 138

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

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

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

    CAS  PubMed  Google Scholar 

  140. 140

    Malhotra, D., Fletcher, A. L. & Turley, S. J. Stromal and hematopoietic cells in secondary lymphoid organs: partners in immunity. Immunol. Rev. 251, 160–176 (2013). References 138–140 are comprehensive reviews of the field of lymph node stromal cell biology.

    PubMed  PubMed Central  Google Scholar 

  141. 141

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

    CAS  PubMed  Google Scholar 

  142. 142

    Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).

    CAS  PubMed  Google Scholar 

  143. 143

    Goc, J., Fridman, W. H., Sautes-Fridman, C. & Dieu-Nosjean, M. C. Characteristics of tertiary lymphoid structures in primary cancers. Oncoimmunology 2, e26836 (2013). This review provides a great introduction to tertiary lymphoid structures in cancer and their various roles in shaping the immune landscape in the TME.

    PubMed  PubMed Central  Google Scholar 

  144. 144

    Wirsing, A. M., Rikardsen, O. G., Steigen, S. E., Uhlin-Hansen, L. & Hadler-Olsen, E. Characterisation and prognostic value of tertiary lymphoid structures in oral squamous cell carcinoma. BMC Clin. Pathol. 14, 38 (2014).

    PubMed  PubMed Central  Google Scholar 

  145. 145

    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).

    CAS  PubMed  Google Scholar 

  146. 146

    Peske, J. D. et al. Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity. Nat. Commun. 6, 7114 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    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).

    CAS  Google Scholar 

  148. 148

    Cipponi, A. et al. Neogenesis of lymphoid structures and antibody responses occur in human melanoma metastases. Cancer Res. 72, 3997–4007 (2012).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank their colleagues for critical discussions about stromal cells in the TME. The authors have made every effort to cover key points and cite important papers, and they regret not having the space to cite all relevant studies.

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Correspondence to Shannon J. Turley.

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S.J.T. and J.L.A. are employees of Genentech. V.C. is an employee at Novartis.

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Glossary

Extracellular matrix

(ECM). A dense network of various molecules that are secreted by cells into the extracellular space. This matrix provides physical support and structure for the cells and organs in addition to serving as a reserve for important signalling molecules such as chemokines.

Pericytes

Contractile cells of mesenchymal origin that are tightly wrapped around the endothelial cells to form blood vessels.

Cancer-immunity cycle

The multi-step process by which T cells are activated in tumour-draining lymph nodes, traffic into tumours and kill tumour cells. There are many points along this cycle that are inhibited by immunosuppressive cells and molecules.

Peripheral tolerance

The control of self-reactive T cells in the periphery.

Extravasation

The process by which an immune cell exits capillaries to enter peripheral tissues.

RIP1–TAG5 mouse model

A mouse model of pancreatic cancer in which the expression of SV40 large T antigen (TAG) is expressed under the control of the rat insulin promoter 1 (RIP1). This results in the inhibition of tumour suppressor genes, which leads to the formation of tumours as the mice age.

Diapedesis

A more specific term for extravasation referring to leukocytes exiting intact blood vessels. Ligands expressed on the surface of blood endothelial cells interact with receptors on immune cells, allowing them to adhere to the vessels and squeeze through.

M2 macrophages

A subset of macrophages that are involved in wound healing and type 2 immune responses, such as allergic immune responses. They are known to generally contribute to a tumour-supporting and immunosuppressive environment in tumours.

Desmoplasia

The growth of dense connective tissue that often occurs as tumours progress from neoplasms. They are marked by high levels of fibroblasts and fibrotic tissue.

Sonic hedgehog

A signalling molecule that is highly upregulated in several solid tumours. Upon its secretion by tumour cells, it can act on cancer-associated fibroblasts and other surrounding cells to promote desmoplasia.

Indoleamine 2,3-dioxygenase

(IDO). An enzyme implicated in the catabolism of tryptophan, and its expression by myeloid cells correlates with immunosuppression by tryptophan deprivation and exposure to the tryptophan catabolite kynurenine.

Cross-presentation

A process by which antigens taken up through endocytosis enter the cytosol and into the MHC class I presentation pathway. This allows for the presentation of extracellular antigens, such as tumour antigens, to CD8+ T cells.

Peripheral tissue antigens

Certain antigens for which expression is generally restricted to a specific tissue, such as the kidney or lung, in an adult animal. These antigens are also expressed by stromal cells in the thymus and peripheral lymph nodes to allow for negative selection of self-reactive T cells.

Mechanotransduction

A process by which cells convert mechanical stimuli into biological signalling processes. This process allows cells to sense changes in the stiffness of the surrounding tissue and respond accordingly by activating various signalling cascades.

Myofibroblasts

A specialized type of fibroblast that has high levels of α-smooth muscle actin and the ability to strongly contract extracellular matrix in its surrounding tissue.

Sentinel lymph nodes

The first set of lymph nodes that drains a tumour. These lymph nodes can potentially contain a high concentration of tumour antigens and inflammatory molecules secreted by the tumour.

Hepatic stellate cells

A population of pericytes present in the liver in close association with the sinusoidal endothelial cells.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous set of cells of myeloid origin that can suppress T cell activity.

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Turley, S., Cremasco, V. & Astarita, J. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol 15, 669–682 (2015). https://doi.org/10.1038/nri3902

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