Host tissue determinants of tumour immunity


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.

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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.


  1. 1.

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

  2. 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).

  3. 3.

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

  4. 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).

  5. 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).

  6. 6.

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

  7. 7.

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

  8. 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).

  9. 9.

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

  10. 10.

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

  11. 11.

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

  12. 12.

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

  13. 13.

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

  14. 14.

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

  15. 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).

  16. 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.

  17. 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).

  18. 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).

  19. 19.

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

  20. 20.

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

  21. 21.

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

  22. 22.

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

  23. 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).

  24. 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.

  25. 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).

  26. 26.

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

  27. 27.

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

  28. 28.

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

  29. 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).

  30. 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.

  31. 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).

  32. 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).

  33. 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).

  34. 34.

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

  35. 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).

  36. 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).

  37. 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).

  38. 38.

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

  39. 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).

  40. 40.

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

  41. 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).

  42. 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).

  43. 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).

  44. 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).

  45. 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).

  46. 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).

  47. 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).

  48. 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).

  49. 49.

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

  50. 50.

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

  51. 51.

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

  52. 52.

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

  53. 53.

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

  54. 54.

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

  55. 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).

  56. 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).

  57. 57.

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

  58. 58.

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

  59. 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).

  60. 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).

  61. 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).

  62. 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).

  63. 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).

  64. 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).

  65. 65.

    Denton, A. E. et al. Type I interferon induces CXCL13 to support ectopic germinal center formation. J. Exp. Med. (2019).

  66. 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.

  67. 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 (2017).

  68. 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).

  69. 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).

  70. 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).

  71. 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).

  72. 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).

  73. 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).

  74. 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).

  75. 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).

  76. 76.

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

  77. 77.

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

  78. 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.

  79. 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.

  80. 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).

  81. 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).

  82. 82.

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

  83. 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).

  84. 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).

  85. 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).

  86. 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).

  87. 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).

  88. 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).

  89. 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).

  90. 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).

  91. 91.

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

  92. 92.

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

  93. 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).

  94. 94.

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

  95. 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).

  96. 96.

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

  97. 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).

  98. 98.

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

  99. 99.

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

  100. 100.

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

  101. 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).

  102. 102.

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

  103. 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).

  104. 104.

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

  105. 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).

  106. 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).

  107. 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).

  108. 108.

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

  109. 109.

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

  110. 110.

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

  111. 111.

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

  112. 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).

  113. 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).

  114. 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.

  115. 115.

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

  116. 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).

  117. 117.

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

  118. 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).

  119. 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).

  120. 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.

  121. 121.

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

  122. 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).

  123. 123.

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

  124. 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).

  125. 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).

  126. 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).

  127. 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).

  128. 128.

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

  129. 129.

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

  130. 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).

  131. 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).

  132. 132.

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

  133. 133.

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

  134. 134.

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

  135. 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).

  136. 136.

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

  137. 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).

  138. 138.

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

  139. 139.

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

  140. 140.

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

  141. 141.

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

  142. 142.

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

  143. 143.

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

  144. 144.

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

  145. 145.

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

  146. 146.

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

  147. 147.

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

  148. 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).

  149. 149.

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

  150. 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).

  151. 151.

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

  152. 152.

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

  153. 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. 154.

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

  155. 155.

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

  156. 156.

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

  157. 157.

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

  158. 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).

  159. 159.

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

  160. 160.

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

  161. 161.

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

  162. 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).

  163. 163.

    Jin, C. et al. Commensal microbiota promote lung cancer development via γδ T cells. Cell (2019). This mouse study shows the impact of the local lung microbiota on lung tumour-associated immune responses.

  164. 164.

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

  165. 165.

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

  166. 166.

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

  167. 167.

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

  168. 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).

  169. 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).

  170. 170.

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

  171. 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).

  172. 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).

  173. 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).

  174. 174.

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

  175. 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.

  176. 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).

  177. 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.

  178. 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).

  179. 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).

  180. 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).

  181. 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).

  182. 182.

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

  183. 183.

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

  184. 184.

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

  185. 185.

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

  186. 186.

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

  187. 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).

  188. 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).

  189. 189.

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

  190. 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).

  191. 191.

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

  192. 192.

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

  193. 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).

  194. 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).

  195. 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).

  196. 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).

  197. 197.

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

  198. 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).

  199. 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).

  200. 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).

  201. 201.

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

  202. 202.

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

  203. 203.

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

  204. 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).

  205. 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).

  206. 206.

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

  207. 207.

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

  208. 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).

  209. 209.

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

  210. 210.

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

  211. 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).

  212. 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).

  213. 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).

  214. 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).

  215. 215.

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

  216. 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).

  217. 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).

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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.

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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.

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Correspondence to Hélène Salmon or Miriam Merad.

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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.

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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.


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.


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.


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.

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Salmon, H., Remark, R., Gnjatic, S. et al. Host tissue determinants of tumour immunity. Nat Rev Cancer 19, 215–227 (2019).

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