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.

Host tissue determinants of tumour immunity

Abstract

Although common evolutionary principles drive the growth of cancer cells regardless of the tissue of origin, the microenvironment in which tumours arise substantially differs across various organ sites. Recent studies have established that, in addition to cell-intrinsic effects, tumour growth regulation also depends on local cues driven by tissue environmental factors. In this Review, we discuss how tissue-specific determinants might influence tumour development and argue that unravelling the tissue-specific contribution to tumour immunity should help the development of precise immunotherapeutic strategies for patients with cancer.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: The cellular and architectural heterogeneity of the tumour microenvironment at distinct cancer sites.
Fig. 2: Cellular contributors to tissue-specific antitumour responses.
Fig. 3: Therapeutic implications of tumour cell-intrinsic and tumour cell-extrinsic factors dependent on tissue specificity.

References

  1. Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl Med. 8, 328rv324 (2016).

    Google Scholar 

  5. Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    PubMed  PubMed Central  Google Scholar 

  7. Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Spranger, S. & Gajewski, T. F. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 18, 139–147 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).

    CAS  PubMed  Google Scholar 

  13. Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    CAS  PubMed  Google Scholar 

  14. Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).

    CAS  PubMed  Google Scholar 

  15. Naito, Y. et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 58, 3491–3494 (1998).

    CAS  PubMed  Google Scholar 

  16. Jimenez-Sanchez, A. et al. Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 170, 927–938 (2017). This is a case report showing that different tumour immune microenvironments can coexist in a single patient at primary and metastatic sites.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Lee, M. et al. Presence of tertiary lymphoid structures determines the level of tumor-infiltrating lymphocytes in primary breast cancer and metastasis. Mod. Pathol. 32, 70–80 (2019).

    CAS  PubMed  Google Scholar 

  18. Lehmann, B. et al. Tumor location determines tissue-specific recruitment of tumor-associated macrophages and antibody-dependent immunotherapy response. Sci. Immunol. 2, eaah6413 (2017).

    PubMed  Google Scholar 

  19. Balkwill, F. R., Capasso, M. & Hagemann, T. The tumor microenvironment at a glance. J. Cell Sci. 125, 5591–5596 (2012).

    CAS  PubMed  Google Scholar 

  20. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Kargl, J. et al. Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nat. Commun. 8, 14381 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Tsujikawa, T. et al. Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis. Cell Rep. 19, 203–217 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ali, H. R., Chlon, L., Pharoah, P. D., Markowetz, F. & Caldas, C. Patterns of immune infiltration in breast cancer and their clinical implications: a gene-expression-based retrospective study. PLOS Med. 13, e1002194 (2016).

    PubMed  PubMed Central  Google Scholar 

  24. Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015). This study highlights the diversity of the TME across tumour types and the impact of tumour heterogeneity on patient outcomes.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Biton, J. et al. TP53, STK11 and EGFR mutations predict tumor immune profile and the response to anti-PD-1 in lung adenocarcinoma. Clin. Cancer Res. 24, 5710–5723 (2018).

    PubMed  Google Scholar 

  26. Lavin, Y. et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 169, 750–765 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Platonova, S. et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res. 71, 5412–5422 (2011).

    CAS  PubMed  Google Scholar 

  28. Bindea, G. et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782–795 (2013).

    CAS  PubMed  Google Scholar 

  29. 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 

  30. Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830 (2018). This is an extensive immunogenomic analysis of over 10,000 patients with 33 different cancer types that is accomplished by utilizing data compiled by TCGA. Also visit CRI iAtlas.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Becht, E. et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 17, 218 (2016).

    PubMed  PubMed Central  Google Scholar 

  32. Heppt, M. V. et al. Immune checkpoint blockade for unresectable or metastatic uveal melanoma: a systematic review. Cancer Treat. Rev. 60, 44–52 (2017).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Komura, T. et al. Inflammatory features of pancreatic cancer highlighted by monocytes/macrophages and CD4+ T cells with clinical impact. Cancer Sci. 106, 672–686 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Beatty, G. L. et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages. Gastroenterology 149, 201–210 (2015).

    CAS  PubMed  Google Scholar 

  37. Royal, R. E. et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Merad, M. & Manz, M. G. Dendritic cell homeostasis. Blood 113, 3418–3427 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bell, D. et al. In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J. Exp. Med. 190, 1417–1426 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 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 

  41. 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).

    CAS  PubMed  Google Scholar 

  42. 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 

  43. Mlecnik, B. et al. Integrative analyses of colorectal cancer show Immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 44, 698–711 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  45. Buisseret, L. et al. Tumor-infiltrating lymphocyte composition, organization and PD-1/ PD-L1 expression are linked in breast cancer. Oncoimmunology 6, e1257452 (2017).

    PubMed  Google Scholar 

  46. Calderaro, J. et al. Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. J. Hepatol. 70, 58–65 (2019).

    PubMed  Google Scholar 

  47. Fridman, W. H., Zitvogel, L., Sautes-Fridman, C. & Kroemer, G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).

    CAS  PubMed  Google Scholar 

  48. Hiraoka, N. et al. Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br. J. Cancer 112, 1782–1790 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Engelhard, V. H. et al. Immune cell infiltration and tertiary lymphoid structures as determinants of antitumor immunity. J. Immunol. 200, 432–442 (2018).

    CAS  PubMed  Google Scholar 

  50. Ladanyi, A. et al. Prognostic impact of B cell density in cutaneous melanoma. Cancer Immunol. Immunother. 60, 1729–1738 (2011).

    CAS  PubMed  Google Scholar 

  51. Martinet, L. et al. High endothelial venules (HEVs) in human melanoma lesions: major gateways for tumor-infiltrating lymphocytes. Oncoimmunology 1, 829–839 (2012).

    PubMed  PubMed Central  Google Scholar 

  52. van Baren, N., Baurain, J. F. & Coulie, P. G. Lymphoid neogenesis in melanoma: what does it tell us? Oncoimmunology 2, e22505 (2013).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  54. Aloisi, F. & Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nat. Rev. Immunol. 6, 205–217 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  56. Marinkovic, T. et al. Interaction of mature CD3+CD4+T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid. J. Clin. Invest. 116, 2622–2632 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sautes-Fridman, C. et al. Tertiary lymphoid structures in cancers: prognostic value, regulation, and manipulation for therapeutic intervention. Front. Immunol. 7, 407 (2016).

    PubMed  PubMed Central  Google Scholar 

  58. Weinstein, A. M. & Storkus, W. J. Therapeutic lymphoid organogenesis in the tumor microenvironment. Adv. Cancer Res. 128, 197–233 (2015).

    PubMed  PubMed Central  Google Scholar 

  59. Colbeck, E. J. et al. Treg depletion licenses T cell-driven HEV neogenesis and promotes tumor destruction. Cancer Immunol. Res. 5, 1005–1015 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kocks, J. R., Davalos-Misslitz, A. C., Hintzen, G., Ohl, L. & Forster, R. Regulatory T cells interfere with the development of bronchus-associated lymphoid tissue. J. Exp. Med. 204, 723–734 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. de Chaisemartin, L. et al. Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer. Cancer Res. 71, 6391–6399 (2011).

    PubMed  Google Scholar 

  62. Fleige, H. et al. IL-17-induced CXCL12 recruits B cells and induces follicle formation in BALT in the absence of differentiated FDCs. J. Exp. Med. 211, 643–651 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Kuroda, E. et al. Inhaled fine particles induce alveolar macrophage death and interleukin-1α release to promote inducible bronchus-associated lymphoid tissue formation. Immunity 45, 1299–1310 (2016).

    CAS  PubMed  Google Scholar 

  64. Silina, K. et al. Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma. Cancer Res. 78, 1308–1320 (2018).

    CAS  PubMed  Google Scholar 

  65. Denton, A. E. et al. Type I interferon induces CXCL13 to support ectopic germinal center formation. J. Exp. Med. https://doi.org/10.1084/JEM.20181216 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Pages, F. et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 391, 2128–2139 (2018). This paper provides international validation of the Immunoscore as a predictive tool for recurrence of disease in CRC.

    PubMed  Google Scholar 

  67. Petitprez, F. et al. PD-L1 expression and CD8+ T cell infiltrate are associated with clinical progression in patients with node positive prostate cancer. Eur. Urol. Focus https://doi.org/10.1016/j.euf.2017.05.013 (2017).

  68. Giraldo, N. A. et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin. Cancer Res. 21, 3031–3040 (2015).

    CAS  PubMed  Google Scholar 

  69. Giraldo, N. A. et al. Tumor-infiltrating and peripheral blood T cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma. Clin. Cancer Res. 23, 4416–4428 (2017).

    CAS  PubMed  Google Scholar 

  70. Roberts, E. W. et al. Critical role for CD103+/CD141+ dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 30, 324–336 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Salmon, H. et al. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Sanchez-Paulete, A. R. et al. Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov. 6, 71–79 (2016).

    CAS  PubMed  Google Scholar 

  74. Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 938 (2014).

    CAS  PubMed  Google Scholar 

  75. 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 

  76. 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 

  77. Remark, R. et al. In-depth tissue profiling using multiplexed immunohistochemical consecutive staining on single slide. Sci. Immunol. 1, aaf6925 (2016).

    Google Scholar 

  78. Barry, K. C. et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 24, 1178–1191 (2018). This is an elegant study showing the importance of the crosstalk between DCs and NK cells in enhancing the antitumour T cell response during immunotherapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014). This is the first study to establish the epigenetic profile of Tr-macs and to show that most of their transcriptional programme is specific to the tissue of residence.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lavin, Y., Mortha, A., Rahman, A. & Merad, M. Regulation of macrophage development and function in peripheral tissues. Nat. Rev. Immunol. 15, 731–744 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Eckl, J. et al. Transcript signature predicts tissue NK cell content and defines renal cell carcinoma subgroups independent of TNM staging. J. Mol. Med. 90, 55–66 (2012).

    CAS  PubMed  Google Scholar 

  82. Coca, S. et al. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 79, 2320–2328 (1997).

    CAS  PubMed  Google Scholar 

  83. Chiossone, L., Dumas, P. Y., Vienne, M. & Vivier, E. Natural killer cells and other innate lymphoid cells in cancer. Nat. Rev. Immunol. 18, 671–688 (2018).

    CAS  PubMed  Google Scholar 

  84. Finnberg, N., Klein-Szanto, A. J. & El-Deiry, W. S. TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis. J. Clin. Invest. 118, 111–123 (2008).

    CAS  PubMed  Google Scholar 

  85. Halfteck, G. G. et al. Enhanced in vivo growth of lymphoma tumors in the absence of the NK-activating receptor NKp46/NCR1. J. Immunol. 182, 2221–2230 (2009).

    CAS  PubMed  Google Scholar 

  86. Bottcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Carrega, P. et al. Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56 bright CD16(-) cells and display an impaired capability to kill tumor cells. Cancer 112, 863–875 (2008).

    PubMed  Google Scholar 

  88. Keren, L. et al. A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging. Cell 174, 1373–1387 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Andre, P. et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Turley, S. J., Cremasco, V. & Astarita, J. L. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat. Rev. Immunol. 15, 669–682 (2015).

    CAS  PubMed  Google Scholar 

  91. Aird, W. C. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ. Res. 100, 158–173 (2007).

    CAS  PubMed  Google Scholar 

  92. Chi, J. T. et al. Endothelial cell diversity revealed by global expression profiling. Proc. Natl Acad. Sci. USA 100, 10623–10628 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Nolan, D. J. et al. Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. Dev. Cell 26, 204–219 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Carmeliet, P. & Jain, R. K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discov. 10, 417–427 (2011).

    CAS  PubMed  Google Scholar 

  96. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    CAS  PubMed  Google Scholar 

  97. 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 

  98. Brem, S. The role of vascular proliferation in the growth of brain tumors. Clin. Neurosurg. 23, 440–453 (1976).

    CAS  PubMed  Google Scholar 

  99. Fidler, I. J. Angiogenic heterogeneity: regulation of neoplastic angiogenesis by the organ microenvironment. J. Natl Cancer Inst. 93, 1040–1041 (2001).

    CAS  PubMed  Google Scholar 

  100. Roberts, W. G. et al. Host microvasculature influence on tumor vascular morphology and endothelial gene expression. Am. J. Pathol. 153, 1239–1248 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Singh, R. K. et al. Organ site-dependent expression of basic fibroblast growth factor in human renal cell carcinoma cells. Am. J. Pathol. 145, 365–374 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Fukumura, D. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 94, 715–725 (1998).

    CAS  PubMed  Google Scholar 

  103. Eppihimer, M. J., Wolitzky, B., Anderson, D. C., Labow, M. A. & Granger, D. N. Heterogeneity of expression of E- and P-selectins in vivo. Circ. Res. 79, 560–569 (1996).

    CAS  PubMed  Google Scholar 

  104. Rafii, S., Butler, J. M. & Ding, B. S. Angiocrine functions of organ-specific endothelial cells. Nature 529, 316–325 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Lee, Y. J. et al. Differential effects of VEGFR-1 and VEGFR-2 inhibition on tumor metastases based on host organ environment. Cancer Res. 70, 8357–8367 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 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  Google Scholar 

  107. 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 

  108. Lee, S. S., Bindokas, V. P. & Kron, S. J. Multiplex three-dimensional optical mapping of tumor immune microenvironment. Sci. Rep. 7, 17031 (2017).

    PubMed  PubMed Central  Google Scholar 

  109. Motz, G. T. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  111. Ishii, G. et al. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem. Biophys. Res. Commun. 309, 232–240 (2003).

    CAS  PubMed  Google Scholar 

  112. Quante, M. et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19, 257–272 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 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 

  114. Arina, A. et al. Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proc. Natl Acad. Sci. USA 113, 7551–7556 (2016). This study uses bone marrow chimaeras and parabiotic mouse experiments to show that CAFs derive mainly from cell precursors present in the local tissue microenvironment.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Buchholz, M. et al. Transcriptome analysis of human hepatic and pancreatic stellate cells: organ-specific variations of a common transcriptional phenotype. J. Mol. Med. 83, 795–805 (2005).

    CAS  PubMed  Google Scholar 

  117. Chang, H. Y. et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc. Natl Acad. Sci. USA 99, 12877–12882 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Higuchi, Y. et al. Gastrointestinal fibroblasts have specialized, diverse transcriptional phenotypes: a comprehensive gene expression analysis of human fibroblasts. PLOS ONE 10, e0129241 (2015).

    PubMed  PubMed Central  Google Scholar 

  119. 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 

  120. Beachley, V. Z. et al. Tissue matrix arrays for high-throughput screening and systems analysis of cell function. Nat. Methods 12, 1197–1204 (2015). This paper presents a proteomic analysis of ECM molecules purified from 11 porcine tissues, highlighting tissue-specific macrophage responses to specific matrix microenvironments.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  122. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  124. Darmanis, S. et al. Single-cell RNA-seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell Rep. 21, 1399–1410 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Fujita, H. et al. α-Smooth muscle actin expressing stroma promotes an aggressive tumor biology in pancreatic ductal adenocarcinoma. Pancreas 39, 1254–1262 (2010).

    CAS  PubMed  Google Scholar 

  126. 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 

  127. D’Aloia, M. M., Zizzari, I. G., Sacchetti, B., Pierelli, L. & Alimandi, M. CAR-T cells: the long and winding road to solid tumors. Cell Death Dis. 9, 282 (2018).

    PubMed  PubMed Central  Google Scholar 

  128. Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  130. 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 

  131. Mayorca-Guiliani, A. E. et al. ISDoT: in situ decellularization of tissues for high-resolution imaging and proteomic analysis of native extracellular matrix. Nat. Med. 23, 890–898 (2017).

    CAS  PubMed  Google Scholar 

  132. 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 

  133. Whatcott, C. J. et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin. Cancer Res. 21, 3561–3568 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 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 

  135. Duda, D. G. et al. Malignant cells facilitate lung metastasis by bringing their own soil. Proc. Natl Acad. Sci. USA 107, 21677–21682 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).

    PubMed  Google Scholar 

  137. Liebl, F. et al. The severity of neural invasion is associated with shortened survival in colon cancer. Clin. Cancer Res. 19, 50–61 (2013).

    CAS  PubMed  Google Scholar 

  138. Zhao, C. M. et al. Denervation suppresses gastric tumorigenesis. Sci. Transl Med. 6, 250ra115 (2014).

    PubMed  PubMed Central  Google Scholar 

  139. Renz, B. W. et al. β2 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell 33, 75–90 (2018).

    CAS  PubMed  Google Scholar 

  140. Gross, E. R. et al. Neuronal serotonin regulates growth of the intestinal mucosa in mice. Gastroenterology 143, 408–417 (2012).

    CAS  PubMed  Google Scholar 

  141. Venkatesh, H. S. et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161, 803–816 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Zahalka, A. H. et al. Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science 358, 321–326 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Ley, S., Weigert, A. & Brune, B. Neuromediators in inflammation—a macrophage/nerve connection. Immunobiology 215, 674–684 (2010).

    CAS  PubMed  Google Scholar 

  144. Gabanyi, I. et al. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell 164, 378–391 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Muller, P. A. et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 1210 (2014).

    CAS  PubMed  Google Scholar 

  146. Wang, H. et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003).

    CAS  PubMed  Google Scholar 

  147. Jobling, P. et al. Nerve-cancer cell cross-talk: a novel promoter of tumor progression. Cancer Res. 75, 1777–1781 (2015).

    CAS  PubMed  Google Scholar 

  148. Grytli, H. H., Fagerland, M. W., Fossa, S. D. & Tasken, K. A. Association between use of beta-blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. Eur. Urol. 65, 635–641 (2014).

    CAS  PubMed  Google Scholar 

  149. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Guilliams, M. et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med. 210, 1977–1992 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    CAS  PubMed  Google Scholar 

  152. Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

    CAS  PubMed  Google Scholar 

  153. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

  154. Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).

    PubMed  PubMed Central  Google Scholar 

  155. Zhu, Y. et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 597 (2017).

    CAS  PubMed  Google Scholar 

  156. Linde, N. et al. Macrophages orchestrate breast cancer early dissemination and metastasis. Nat. Commun. 9, 21 (2018).

    PubMed  PubMed Central  Google Scholar 

  157. Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Paulos, C. M. et al. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J. Clin. Invest. 117, 2197–2204 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971–976 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Costello, E. K. et al. Bacterial community variation in human body habitats across space and time. Science 326, 1694–1697 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Naik, S. et al. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520, 104–108 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Man, W. H., de Steenhuijsen Piters, W. A. & Bogaert, D. The microbiota of the respiratory tract: gatekeeper to respiratory health. Nat. Rev. Microbiol. 15, 259–270 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Jin, C. et al. Commensal microbiota promote lung cancer development via γδ T cells. Cell https://doi.org/10.1016/j.cell.2018.12.040 (2019). This mouse study shows the impact of the local lung microbiota on lung tumour-associated immune responses.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).

    PubMed  PubMed Central  Google Scholar 

  165. Attalla, K., Sfakianos, J. P. & Galsky, M. D. Current role of checkpoint inhibitors in urologic cancers. Cancer Treat. Res. 175, 241–258 (2018).

    PubMed  Google Scholar 

  166. Solinas, C. et al. Targeting immune checkpoints in breast cancer: an update of early results. ESMO Open 2, e000255 (2017).

    PubMed  PubMed Central  Google Scholar 

  167. Garber, K. Driving T cell immunotherapy to solid tumors. Nat. Biotechnol. 36, 215–219 (2018).

    CAS  PubMed  Google Scholar 

  168. Long, K. B. et al. CAR T cell therapy of non-hematopoietic malignancies: detours on the road to clinical success. Front. Immunol. 9, 2740 (2018).

    PubMed  PubMed Central  Google Scholar 

  169. Ozdemir, B. C. et al. The molecular signature of the stroma response in prostate cancer-induced osteoblastic bone metastasis highlights expansion of hematopoietic and prostate epithelial stem cell niches. PLOS ONE 9, e114530 (2014).

    PubMed  PubMed Central  Google Scholar 

  170. Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Yao, X. et al. Levels of peripheral CD4+FoxP3+ regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood 119, 5688–5696 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Gnjatic, S. et al. NY-ESO-1: review of an immunogenic tumor antigen. Adv. Cancer Res. 95, 1–30 (2006).

    CAS  PubMed  Google Scholar 

  175. Shukla, S. A. et al. Cancer-germline antigen expression discriminates clinical outcome to CTLA-4 blockade. Cell 173, 624–633 (2018). This study shows that MAGEA expression and ensuing autophagy suppression in metastatic melanoma predict resistance to CTLA4 blockade, but not PD1 blockade, independently of neoantigen load.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).

    CAS  PubMed  Google Scholar 

  177. Spranger, S. et al. Density of immunogenic antigens does not explain the presence or absence of the T cell-inflamed tumor microenvironment in melanoma. Proc. Natl Acad. Sci. USA 113, E7759–E7768 (2016). This study shows that melanomas with or without T cell signatures have similar numbers of predicted neoantigens owing to point mutations, suggesting that other factors may dictate spontaneous T cell infiltration.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Braga, W. M. et al. Is there any relationship between gene expression of tumor antigens and CD4+ T cells in multiple myeloma? Immunotherapy 6, 569–575 (2014).

    CAS  PubMed  Google Scholar 

  179. Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48–61 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Maby, P. et al. Correlation between density of CD8+ T cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy. Cancer Res. 75, 3446–3455 (2015).

    CAS  PubMed  Google Scholar 

  181. Coutinho, I., Day, T. K., Tilley, W. D. & Selth, L. A. Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence. Endocr. Relat. Cancer 23, T179–T197 (2016).

    CAS  PubMed  Google Scholar 

  182. Kufe, D. W. Mucins in cancer: function, prognosis and therapy. Nat. Rev. Cancer 9, 874–885 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Zitvogel, L., Ayyoub, M., Routy, B. & Kroemer, G. Microbiome and anticancer immunosurveillance. Cell 165, 276–287 (2016).

    CAS  PubMed  Google Scholar 

  184. Molon, B. et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J. Exp. Med. 208, 1949–1962 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Gao, X. & McDermott, D. F. Combinations of bevacizumab with immune checkpoint inhibitors in renal cell carcinoma. Cancer J. 24, 171–179 (2018).

    CAS  PubMed  Google Scholar 

  186. Zitvogel, L. et al. The anticancer immune response: indispensable for therapeutic success? J. Clin. Invest. 118, 1991–2001 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Tsuda, N. et al. Taxol increases the amount and T cell activating ability of self-immune stimulatory multimolecular complexes found in ovarian cancer cells. Cancer Res. 67, 8378–8387 (2007).

    CAS  PubMed  Google Scholar 

  188. Jiang, W., Chan, C. K., Weissman, I. L., Kim, B. Y. S. & Hahn, S. M. Immune priming of the tumor microenvironment by radiation. Trends Cancer 2, 638–645 (2016).

    PubMed  Google Scholar 

  189. Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Smyth, M. J., Ngiow, S. F., Ribas, A. & Teng, M. W. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat. Rev. Clin. Oncol. 13, 143–158 (2016).

    CAS  PubMed  Google Scholar 

  191. Bosman, F. T., Havenith, M. & Cleutjens, J. P. Basement membranes in cancer. Ultrastruct. Pathol. 8, 291–304 (1985).

    CAS  PubMed  Google Scholar 

  192. Liotta, L. A. et al. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 284, 67–68 (1980).

    CAS  PubMed  Google Scholar 

  193. Dorudi, S., Sheffield, J. P., Poulsom, R., Northover, J. M. & Hart, I. R. E-Cadherin expression in colorectal cancer. An immunocytochemical and in situ hybridization study. Am. J. Pathol. 142, 981–986 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Hoover, K. B., Liao, S. Y. & Bryant, P. J. Loss of the tight junction MAGUK ZO-1 in breast cancer: relationship to glandular differentiation and loss of heterozygosity. Am. J. Pathol. 153, 1767–1773 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Pignatelli, M. et al. Loss of membranous E-cadherin expression in pancreatic cancer: correlation with lymph node metastasis, high grade, and advanced stage. J. Pathol. 174, 243–248 (1994).

    CAS  PubMed  Google Scholar 

  196. Wolf, K., Muller, R., Borgmann, S., Brocker, E. B. & Friedl, P. Amoeboid shape change and contact guidance: T-lymphocyte crawling through fibrillar collagen is independent of matrix remodeling by MMPs and other proteases. Blood 102, 3262–3269 (2003).

    CAS  PubMed  Google Scholar 

  197. Shan, M. et al. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342, 447–453 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Price-Schiavi, S. A. et al. Rat Muc4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for herceptin resistance. Int. J. Cancer 99, 783–791 (2002).

    CAS  PubMed  Google Scholar 

  199. Komatsu, M., Yee, L. & Carraway, K. L. Overexpression of sialomucin complex, a rat homologue of MUC4, inhibits tumor killing by lymphokine-activated killer cells. Cancer Res. 59, 2229–2236 (1999).

    CAS  PubMed  Google Scholar 

  200. Brossart, P. et al. The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC1-specific cytotoxic T-lymphocytes. Cancer Res. 61, 6846–6850 (2001).

    CAS  PubMed  Google Scholar 

  201. Claes, A., Idema, A. J. & Wesseling, P. Diffuse glioma growth: a guerilla war. Acta Neuropathol. 114, 443–458 (2007).

    PubMed  PubMed Central  Google Scholar 

  202. Eroglu, Z. et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature 553, 347–350 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Havran, W. L. & Jameson, J. M. Epidermal T cells and wound healing. J. Immunol. 184, 5423–5428 (2010).

    CAS  PubMed  Google Scholar 

  204. Clark, R. A. et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci. Transl Med. 4, 117ra117 (2012).

    Google Scholar 

  205. Gasteiger, G., Fan, X., Dikiy, S., Lee, S. Y. & Rudensky, A. Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science 350, 981–985 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Peng, H. et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Invest. 123, 1444–1456 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Kumamoto, T. et al. Hair follicles serve as local reservoirs of skin mast cell precursors. Blood 102, 1654–1660 (2003).

    CAS  PubMed  Google Scholar 

  208. Enamorado, M. et al. Enhanced anti-tumour immunity requires the interplay between resident and circulating memory CD8+ T cells. Nat. Commun. 8, 16073 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Malik, B. T. et al. Resident memory T cells in the skin mediate durable immunity to melanoma. Sci. Immunol. 2, eaam6346 (2017).

    PubMed  PubMed Central  Google Scholar 

  210. Park, S. L. et al. Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin. Nature 565, 366–371 (2019).

    PubMed  Google Scholar 

  211. Djenidi, F. et al. CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J. Immunol. 194, 3475–3486 (2015).

    CAS  PubMed  Google Scholar 

  212. Edwards, J. et al. CD103+ tumor-resident CD8+ T cells are associated with improved survival in immunotherapy-naive melanoma patients and expand significantly during anti-PD-1 treatment. Clin. Cancer Res. 24, 3036–3045 (2018).

    CAS  PubMed  Google Scholar 

  213. Webb, J. R., Milne, K., Watson, P., Deleeuw, R. J. & Nelson, B. H. Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer. Clin. Cancer Res. 20, 434–444 (2014).

    CAS  PubMed  Google Scholar 

  214. Bordry, N. et al. Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma. Oncoimmunology 7, e1462878 (2018).

    PubMed  PubMed Central  Google Scholar 

  215. Lund, A. W. et al. Lymphatic vessels regulate immune microenvironments in human and murine melanoma. J. Clin. Invest. 126, 3389–3402 (2016).

    PubMed  PubMed Central  Google Scholar 

  216. Podgrabinska, S. et al. Inflamed lymphatic endothelium suppresses dendritic cell maturation and function via Mac-1/ICAM-1-dependent mechanism. J. Immunol. 183, 1767–1779 (2009).

    CAS  PubMed  Google Scholar 

  217. 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  Google Scholar 

Download references

Acknowledgements

The laboratory of M.M. is supported by funding from R01 CA154947, R01 CA190400, R01 AI113221, U24 AI118644, U19 AI117873 and U19 AI128949. S.G. is supported by R01 CA224319 and CA190174 grants. The authors thank G. Akturk, A. O. Kamphorst and J. Martin for helpful comments, and S. Maskey for her help with generating figures.

Author information

Authors and Affiliations

Authors

Contributions

H.S., R.R., S.G. and M.M. contributed to researching data, discussing content and writing the article. H.S. and M.M. reviewed and edited the manuscript.

Corresponding authors

Correspondence to Hélène Salmon or Miriam Merad.

Ethics declarations

Competing interests

H.S. receives research funding from Takeda and Genentech. R.R. is an employee of Innate Pharma. S.G. reports consultancy and/or advisory roles for Merck, Neon Therapeutics and OncoMed and research funding from Bristol-Myers Squibb, Genentech, Immune Design, Agenus, Janssen R&D and Pfizer. M.M. receives funding from Regeneron, Takeda, Genentech and Boehringer Ingelheim.

Additional information

Publisher’s note

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

Related links

CRI iAtlas: https://www.cri-iatlas.org

Glossary

Uveal melanoma

The most common primary cancer of the eye in adults, arising from melanocytes located in the uvea (which comprises the choroid, the ciliary body and the iris).

Peripheral node addressin

(PNAd). A sulfated protein at the surface of high endothelial venules in secondary and tertiary lymphoid tissues that is crucial for the homing of naive and central memory T cells.

Lymphoid neogenesis

The de novo formation of ectopic lymphoid structures within peripheral tissues during chronic inflammation.

Lymphotoxin

A cytokine expressed by lymphoid tissue inducer cells and lymphocytes. In lymphoid neogenesis, lymphotoxin-α (LTα) forms a complex with LTβ to bind to the LTβ receptor on stromal cells, leading to nuclear factor-κB (NF-κB) signalling, which promotes the production of chemokines necessary for T cell and B cell recruitment.

Parabiosis

The surgical union of two organisms leading to the sharing of blood circulation, enabling the assessment of the recruitment and contribution of blood circulating cells to a cellular compartment in a tissue or lesion.

β-blockers

Drugs blocking β-adrenergic signalling on nerve cells, causing blood vessels to relax and dilate; these are commonly used to treat high blood pressure and other cardiac conditions.

Tumour agnostic

Compatible with any tumour type.

Multivalent vaccines

Vaccines designed to immunize against two or more antigens.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Salmon, H., Remark, R., Gnjatic, S. et al. Host tissue determinants of tumour immunity. Nat Rev Cancer 19, 215–227 (2019). https://doi.org/10.1038/s41568-019-0125-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-019-0125-9

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing