The role of the tumor vasculature in the host immune response: Implications for therapeutic strategies targeting the tumor microenvironment

Frontiers in Immunology

Volumn 7, Issue DEC, 2016, Pages

  Hendry, Shona A ^a,b   Farnsworth, Rae H ^a   Solomon, Benjamin ^a   Achen, Marc G ^a,b   Stacker, Steven A ^a,b   Fox, Stephen B ^a  

^a PETER MACCALLUM CANCER CENTRE   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

Angiogenesis inhibitors; Endothelial cells; Immunotherapy; Lymphatic endothelial cells; Tumor immune evasion

Indexed keywords

ANGIOGENESIS INHIBITOR; ANGIOGENIC FACTOR; ANTHRACYCLINE; CHEMOKINE RECEPTOR CXCR3; FIBROBLAST GROWTH FACTOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERCELLULAR ADHESION MOLECULE 1; LYMPHOCYTE FUNCTION ASSOCIATED ANTIGEN 1; TISSUE ANTIGEN; TRASTUZUMAB; TUMOR ANTIGEN; VASCULOTROPIN A; VASCULOTROPIN C; VASCULOTROPIN D; VERY LATE ACTIVATION ANTIGEN 4;

BREAST CANCER; CANCER CHEMOTHERAPY; CANCER GROWTH; CELL DIFFERENTIATION; CELL INFILTRATION; CELL MIGRATION; COLORECTAL CANCER; HUMAN; IMMUNE EVASION; IMMUNE RESPONSE; IMMUNOSUPPRESSIVE TREATMENT; IMMUNOTHERAPY; KIDNEY CARCINOMA; LYMPHANGIOGENESIS; MELANOMA; METASTASIS; MUTATION; REVIEW; TISSUE PRESSURE; TUMOR ASSOCIATED LEUKOCYTE; TUMOR MICROENVIRONMENT; TUMOR VASCULARIZATION;

EID: 85009354112     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2016.00621     Document Type: Review

References (238)

1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell (2011) 144(5):646-74. doi:10.1016/j.cell.2011.02.013
2. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med (2010) 363(8):711-23. doi:10.1056/NEJMoa1003466
3. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med (2015) 372(4):320-30. doi:10.1056/NEJMoa1412082
4. Rosenberg JE, Hoffman-Censits J, Powles T, Van der Heijden ME, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet (2016) 387:1909-20. doi:10.1016/S0140-6736(16)00561-4
5. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med (2015) 372(4):311-9. doi:10.1056/NEJMoa1411087
6. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med (2015) 373(17):1627-39. doi:10.1056/NEJMoa1507643
7. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med (2015) 373(2):123-35. doi:10.1056/NEJMoa1504627
8. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med (2015) 372(21):2018-28. doi:10.1056/NEJMoa1501824
9. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med (2016) 374(26):2542-52. doi:10.1056/NEJMoa1603702
10. Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol (2016) 17(7):956-65. doi:10.1016/s1470-2045(16)30066-3
11. Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood (2015) 125(26):4017-23. doi:10.1182/blood-201412-580068
12. Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer (2016) 16(5):275-87. doi:10.1038/nrc.2016.36
13. Newick K, Moon E, Albelda SM. Chimeric antigen receptor T-cell therapy for solid tumors. Mol Ther Oncolytics (2016) 3:16006. doi:10.1038/mto.2016.6
14. Quigley DA, Kristensen V. Predicting prognosis and therapeutic response from interactions between lymphocytes and tumor cells. Mol Oncol (2015) 9(10):2054-62. doi:10.1016/j.molonc.2015.10.003
15. Teng MW, Galon J, Fridman WH, Smyth MJ. From mice to humans: developments in cancer immunoediting. J Clin Invest (2015) 125(9):3338-46. doi:10.1172/JCI80004
16. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol (2013) 14(10):1014-22. doi:10.1038/ni.2703
17. Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer (2014) 14(2):135-46. doi:10.1038/nrc3670
18. Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS, et al. Characterisation of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med (1999) 5(6):677-85. doi:10.1038/9525
19. Gros A, Parkhurst MR, Tran E, Pasetto A, Robbins PF, Ilyas S, et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med (2016) 22(4):433-8. doi:10.1038/nm.4051
20. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer (2012) 12(4):298-306. doi:10.1038/nrc3245
21. Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, et al. Towards the introduction of the 'Immunoscore' in the classification of malignant tumours. J Pathol (2014) 232(2):199-209. doi:10.1002/path.4287
22. Savas P, Salgado R, Denkert C, Sotiriou C, Darcy PK, Smyth MJ, et al. Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat Rev Clin Oncol (2016) 13(4):228-41. doi:10.1038/nrclinonc.2015.215
23. Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol (2013) 25(2):268-76. doi:10.1016/j.coi.2013.02.009
24. Teng MW, Ngiow SF, Ribas A, Smyth MJ. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res (2015) 75(11):2139-45. doi:10.1158/0008-5472.CAN-15-0255
25. Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature (2016) 531(7592):47-52. doi:10.1038/nature16965
26. Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med (2015) 21(11):1350-6. doi:10.1038/nm.3967
27. Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell (2015) 161(7):1681-96. doi:10.1016/j.cell.2015.05.044
28. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs working group 2014. Ann Oncol (2015) 26(2):259-71. doi:10.1093/annonc/mdu450
29. Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol (2012) 30(21):2678-83. doi:10.1200/JCO.2011.37.8539
30. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med (2015) 372(26):2509-20. doi:10.1056/NEJMoa1500596
31. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature (2013) 500(7463):415-21. doi:10.1038/nature12477
32. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med (2014) 371(23):2189-99. doi:10.1056/NEJMoa1406498
33. Rivzi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science (2015) 348(6230):124-8. doi:10.1126/science.aaa1348
34. Remark R, Becker C, Gomez JE, Damotte D, Dieu-Nosjean MC, Sautes-Fridman C, et al. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am J Respir Crit Care Med (2015) 191(4):377-90. doi:10.1164/rccm.201409-1671PP
35. Slaney CY, Kershaw MH, Darcy PK. Trafficking of T cells into tumors. Cancer Res (2014) 74(24):7168-74. doi:10.1158/0008-5472.CAN-14-2458
36. Masopust D, Schenkel JM. The integration of T cell migration, differentiation and function. Nat Rev Immunol (2013) 13(5):309-20. doi:10.1038/nri3442
37. Mulligan AM, Raitman I, Feeley L, Pinnaduwage D, Nguyen LT, O'Malley FP, et al. Tumoral lymphocytic infiltration and expression of the chemokine CXCL10 in breast cancers from the Ontario familial breast cancer registry. Clin Cancer Res (2013) 19(2):336-46. doi:10.1158/1078-0432.CCR-11-3314
38. Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res (2009) 69(7):3077-85. doi:10.1158/0008-5472.CAN-08-2281
39. Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med (2011) 208(10):1949-62. doi:10.1084/jem.20101956
40. Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science (2015) 348(6230):74-80. doi:10.1126/science.aaa6204
41. Noman MZ, Hasmim M, Messai Y, Terry S, Kieda C, Janji B, et al. Hypoxia: a key player in antitumor immune response. A review in the theme: cellular responses to hypoxia. Am J Physiol Cell Physiol (2015) 309(9):C569-79. doi:10.1152/ajpcell.00207.2015
42. Molon B, Cali B, Viola A. T cells and cancer: how metabolism shapes immunity. Front Immunol (2016) 7:20. doi:10.3389/fimmu.2016.00020
43. Munn DH, Mellor AL. Indoleamine 2, 3 dioxygenase and metabolic control of immune responses. Trends Immunol (2013) 34(3):137-43. doi:10.1016/j.it.2012.10.001
44. Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci U S A (2010) 107(46):19961-6. doi:10.1073/pnas.1014465107
45. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2, 3-dioxygenase. Immunity (2005) 22(5):633-42. doi:10.1016/j.immuni.2005.03.013
46. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor-chain and induce a regulatory phenotype in naive T cells. J Immunol (2006) 176(11):6752-61. doi:10.4049/jimmunol.176.11.6752
47. Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H, et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2, 3-dioxygenase. J Clin Invest (2007) 117(9):2570-82. doi:10.1172/JCI31911
48. Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2, 3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med (2013) 210(7):1389-402. doi:10.1084/jem.20130066
49. Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine 2, 3-dioxygenase pathway in cancer. J Immunother Cancer (2015) 3:51. doi:10.1186/s40425-015-0094-9
50. Bronte V, Zanovello P. Regulation of immune responses by l-arginine metabolism. Nat Rev Immunol (2005) 5(8):641-54. doi:10.1038/nri1668
51. Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res (2004) 64:5839-49. doi:10.1158/0008-5472.CAN-04-0465
52. Kostourou V, Cartwright JE, Johnstone AP, Boult JK, Cullis ER, Whitley G, et al. The role of tumour-derived iNOS in tumour progression and angiogenesis. Br J Cancer (2011) 104(1):83-90. doi:10.1038/sj.bjc.6606034
53. Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res (2009) 69(4):1553-60. doi:10.1158/0008-5472.CAN-08-1921
54. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer (2012) 12(4):252-64. doi:10.1038/nrc3239
55. Walker LS, Abbas AK. The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol (2002) 2(1):11-9. doi:10.1038/nri701
56. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med (2012) 366(26):2443-54. doi:10.1056/NEJMoa1200690
57. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med (2012) 366(26):2455-65. doi:10.1056/NEJMoa1200694
58. Tang H, Wang Y, Chlewicki LK, Zhang Y, Guo J, Liang W, et al. Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell (2016) 29(3):285-96. doi:10.1016/j.ccell.2016.02.004
59. Kershaw MH, Westwood JA, Darcy PK. Gene-engineered T cells for cancer therapy. Nat Rev Cancer (2013) 13(8):525-41. doi:10.1038/nrc3565
60. Mukai S, Kjaergaard J, Shu S, Plautz GE. Infiltration of tumors by systemically transferred tumor-reactive T lymphocytes is required for antitumor efficacy. Cancer Res (1999) 59(20):5245-9.
61. Craddock JA, Lu A, Bear A, Pule M, Brenner MK, Rooney CM, et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother (2010) 33(8):780-8. doi:10.1097/CJI.0b013e3181ee6675
62. Adusumilli PS, Cherkassky L, Villena-Vargas J, Colovos C, Servais E, Plotkin J, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med (2014) 6(261):261ra151. doi:10.1126/scitranslmed.3010162
63. Beavis PA, Slaney CY, Kershaw MH, Gyorki D, Neeson PJ, Darcy PK. Reprogramming the tumor microenvironment to enhance adoptive cellular therapy. Semin Immunol (2016) 28(1):64-72. doi:10.1016/j.smim.2015.11.003
64. Ganss R, Hanahan D. Tumor microenvironment can restrict the effectiveness of activated antitumour lymphocytes. Cancer Res (1998) 58:4673-81.
65. Pober JS, Tellides G. Participation of blood vessel cells in human adaptive immune responses. Trends Immunol (2012) 33(1):49-57. doi:10.1016/j.it.2011.09.006
66. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol (2007) 7(9):678-89. doi:10.1038/nri2156
67. Lawrence MB, Kansas GS, Kunkel EJ, Ley K. Threshold levels of fluid shear promote leukocyte adhesion through selectins (CD62L, P, E). J Cell Biol (1997) 136:717-27. doi:10.1083/jcb.136.3.717
68. Rothlein R, Dustin ML, Marlin SD, Springer TA. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J Immunol (1986) 137:1270-4.
69. Osborn L, Hession C, Tizard R, Vassallo C, Luhowskyj S, Chi-Rosso G, et al. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell (1989) 59:1203-11. doi:10.1016/0092-8674(89)90775-7
70. Dustin ML, Rothlein R, Bhan AK, Dinarello CA, Springer TA. Induction by IL-1 and interferon-γ: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol (1986) 186:5024-33.
71. Elices MJ, Osborn L, Takada Y, Crouse C, Luhowskyj S, Hemler ME, et al. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell (1990) 60:577-84. doi:10.1016/0092-8674(90)90661-W
72. Springer TA. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol (1995) 57:827-72. doi:10.1146/annurev.ph.57.030195.004143
73. Muller WA. Mechanisms of leukocyte transendothelial migration. Annu Rev Pathol (2011) 6:323-44. doi:10.1146/annurev-pathol-011110-130224
74. Clark RA, Huang SJ, Murphy GF, Mollet IG, Hijnen D, Muthukuru M, et al. Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. J Exp Med (2008) 205(10):2221-34. doi:10.1084/jem.20071190
75. Afanasiev OK, Nagase K, Simonson W, Vandeven N, Blom A, Koelle DM, et al. Vascular E-selectin expression correlates with CD8 lymphocyte infiltration and improved outcome in Merkel cell carcinoma. J Invest Dermatol (2013) 133(8):2065-73. doi:10.1038/jid.2013.36
76. Bouma-ter Steege JC, Baeten CI, Thijssen VL, Satijn SA, Verhoeven IC, Hillen HF, et al. Angiogenic profile of breast carcinoma determines leukocyte infiltration. Clin Cancer Res (2004) 10:7171-8. doi:10.1158/1078-0432.CCR-04-0742
77. Springer TA. Adhesion receptors of the immune system. Nature (1990) 34:425-34. doi:10.1038/346425a0
78. Choi J, Enis DR, Koh KP, Shiao SL, Pober JS. T lymphocyte-endothelial cell interactions. Annu Rev Immunol (2004) 22:683-709. doi:10.1146/annurev.immunol.22.012703.104639
79. Pober JS, Gimbrone MA, Lapierre LA, Mendrick DL, Fiers W, Rothlein R, et al. Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol (1986) 137:1893-6.
80. Crusz SM, Balkwill FR. Inflammation and cancer: advances and new agents. Nat Rev Clin Oncol (2015) 12(10):584-96. doi:10.1038/nrclinonc.2015.105
81. Piali L, Fichtel A, Terpe H, Imhof BA, Gisler RH. Endothelial vascular cell adhesion molecule1 expression is suppressed by melanoma and carcinoma. J Exp Med (1995) 181:811-6. doi:10.1084/jem.181.2.811
82. Weishaupt C, Munoz KN, Buzney E, Kupper TS, Fuhlbrigge RC. T-cell distribution and adhesion receptor expression in metastatic melanoma. Clin Cancer Res (2007) 13(9):2549-56. doi:10.1158/1078-0432.CCR-06-2450
83. Griffioen AW, Damen CA, Blijham GH, Groenewegen G. Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood (1996) 88(2):667-73.
84. Griffioen AW, Damen CA, Martinotti S, Blijham GH, Groenewegen G. Endothelial intercellular adhesion molecule 1 is suppressed in malignancies: the role of angiogenic factors. Cancer Res (1996) 56:1111-7.
85. Dirkx AE, Oude Egbrink MG, Kuijpers MJE, van der Niet ST, Heijnen VVT, Bouma-ter Steege JC, et al. Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Res (2003) 63:2322-9.
86. Horsman MR, Vaupel P. Pathophysiological basis for the formation of the tumor microenvironment. Front Oncol (2016) 6:66. doi:10.3389/fonc.2016.00066
87. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science (1989) 246:1306-9. doi:10.1126/science.2479986
88. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science (1989) 246:1309-12. doi:10.1126/science.2479987
89. Zhang H, Issekutz AC. Down modulation of monocyte transendothelial migration and endothelial adhesion molecule expression by fibroblast growth factor. Am J Pathol (2002) 160(6):2219-30. doi:10.1016/S0002-9440(10)61169-8
90. Griffioen AW, Relou IAM, Gallardo Torres HI, Damen CA, Martinotti S, de Graaf JC, et al. The angiogenic factor bFGF impairs leukocyte adhesion and rolling under flow conditions. Angiogenesis (1998) 2:235-43. doi:10.1023/A:1009289303145
91. Maksan S, Araib PM, Ryschich E, Gebhard MM, Schmidt J. Immune escape mechanism: defective resting and stimulated leukocyte-endothelium interaction in hepatocellular carcinoma of the rat. Dig Dis Sci (2004) 49(5):859-65. doi:10.1023/B:DDAS.0000030100.05979.b7
92. Tromp SC, Oude Egbrink MG, Dings RP, van Velzen S, Slaaf DW, Hillen HFP, et al. Tumor angiogenesis factors reduce leukocyte adhesion in vivo. Int Immunol (2000) 12(5):671-6. doi:10.1093/intimm/12.5.671
93. Flati V, Pastore LI, Griffioen AW, Satijn SA, Toniato E, D'Alimonte I, et al. Endothelial cell anergy is mediated by bFGF through the sustained activation of p38-MAPK and NFkB inhibition. Int J Immunopathol Pharmacol (2006) 19(4):761-73.
94. Dirkx AE, Oude Egbrink MG, Castermans K, van der Schaft DW, Thijssen VL, Dings RP, et al. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. FASEB J (2006) 20(6):621-30. doi:10.1096/fj.05-4493com
95. Griffioen AW, Damen CA, Mayo KH, Barendsz-Jansen A, Martinotti S, Blijham GH, et al. Angiogenesis inhibitors overcome tumor induced endothelial cell anergy. Int J Cancer (1999) 80:315-9. doi:10.1002/(SICI)1097-0215(19990118)80:2<315::AID-IJC23>3.0.CO;2-L
96. Limaverde-Sousa G, Sternberg C, Ferreira CG. Antiangiogenesis beyond VEGF inhibition: a journey from antiangiogenic single-target to broad-spectrum agents. Cancer Treat Rev (2014) 40(4):548-57. doi:10.1016/j.ctrv.2013.11.009
97. Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res (2010) 70(15):6171-80. doi:10.1158/0008-5472.CAN-10-0153
98. Tao L, Huang G, Shi S, Chen L. Bevacizumab improves the antitumor efficacy of adoptive cytokine-induced killer cells therapy in non-small cell lung cancer models. Med Oncol (2014) 31(1):777. doi:10.1007/s12032-013-0777-3
99. Li B, Lalani AS, Harding TC, Luan B, Koprivnikar K, Huan Tu G, et al. Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clin Cancer Res (2006) 12(22):6808-16. doi:10.1158/1078-0432.CCR-06-1558
100. Manning EA, Ullman JG, Leatherman JM, Asquith JM, Hansen TR, Armstrong TD, et al. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res (2007) 13(13):3951-9. doi:10.1158/1078-0432.CCR-07-0374
101. Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A (2012) 109(43):17561-6. doi:10.1073/pnas.1215397109
102. Huang KW, Wu HL, Lin HL, Liang PC, Chen PJ, Chen SH, et al. Combining antiangiogenic therapy with immunotherapy exerts better therapeutical effects on large tumors in a woodchuck hepatoma model. Proc Natl Acad Sci U S A (2010) 107(33):14769-74. doi:10.1073/pnas.1009534107
103. Chan SF, Wang HT, Huang KW, Torng PL, Lee HI, Hwang LH. Anti-angiogenic therapy renders large tumors vulnerable to immunotherapy via reducing immunosuppression in the tumor microenvironment. Cancer Lett (2012) 320(1):23-30. doi:10.1016/j.canlet.2012.01.024
104. Shi S, Wang R, Chen Y, Song H, Chen L, Huang G. Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models. PLoS One (2013) 8(6):e65757. doi:10.1371/journal.pone.0065757
105. Dings RP, Vang KB, Castermans K, Popescu F, Zhang Y, Oude Egbrink MG, et al. Enhancement of T-cell-mediated antitumor response: angiostatic adjuvant to immunotherapy against cancer. Clin Cancer Res (2011) 17(10):3134-45. doi:10.1158/1078-0432.CCR-10-2443
106. Huang X, Wong MK, Yi H, Watkins S, Laird AD, Wolf SF, et al. Combined therapy of local and metastatic 4T1 breast tumor in mice using SU6668, an inhibitor of angiogenic receptor tyrosine kinases, and the immunostimulator B7.2-IgG fusion protein. Cancer Res (2002) 62:5727-35.
107. Farsaci B, Donahue RN, Coplin MA, Grenga I, Lepone LM, Molinolo AA, et al. Immune consequences of decreasing tumor vasculature with antiangiogenic tyrosine kinase inhibitors in combination with therapeutic vaccines. Cancer Immunol Res (2014) 2(11):1090-102. doi:10.1158/2326-6066.CIR-14-0076
108. Johansson A, Hamzah J, Payne CJ, Ganss R. Tumor-targeted TNFalpha stabilizes tumor vessels and enhances active immunotherapy. Proc Natl Acad Sci U S A (2012) 109(20):7841-6. doi:10.1073/pnas.1118296109
109. Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res (2014) 2(7):632-42. doi:10.1158/2326-6066.CIR-14-0053
110. Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun (2016) 7:12624. doi:10.1038/ncomms12624
111. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res (1999) 5:2963-70.
112. Renner DN, Malo CS, Jin F, Parney IF, Pavelko KD, Johnson AJ. Improved treatment efficacy of antiangiogenic therapy when combined with picornavirus vaccination in the GL261 glioma model. Neurotherapeutics (2016) 13(1):226-36. doi:10.1007/s13311-015-0407-1
113. Shi S, Chen L, Huang G. Antiangiogenic therapy improves the antitumor effect of adoptive cell immunotherapy by normalizing tumor vasculature. Med Oncol (2013) 30(4):698. doi:10.1007/s12032-013-0698-1
114. Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res (2009) 69(6):2514-22. doi:10.1158/0008-5472.CAN-08-4709
115. Yu N, Fu S, Xu Z, Liu Y, Hao J, Zhang A, et al. Synergistic antitumor responses by combined GITR activation and sunitinib in metastatic renal cell carcinoma. Int J Cancer (2016) 138(2):451-62. doi:10.1002/ijc.29713
116. Grenga I, Kwilas AR, Donahue RN, Farsaci B, Hodge JW. Inhibition of the angiopoietin/Tie2 axis induces immunogenic modulation, which sensitizes human tumor cells to immune attack. J Immunother Cancer (2015) 3:52. doi:10.1186/s40425-015-0096-7
117. Carter T, Shaw H, Cohn-Brown D, Chester K, Mulholland P. Ipilimumab and bevacizumab in glioblastoma. Clin Oncol (R Coll Radiol) (2016) 28(10):622-6. doi:10.1016/j.clon.2016.04.042
118. Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A (1998) 95:548-53. doi:10.1073/pnas.95.2.548
119. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J (1996) 15:290-8.
120. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med (2001) 7:186-91. doi:10.1038/84635
121. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med (2001) 7:192-8. doi:10.1038/84643
122. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J (2001) 20:672-82. doi:10.1093/emboj/20.4.672
123. Achen MG, Williams RA, Minekus MP, Thornton GE, Stenvers K, Rogers PAW, et al. Localisation of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumor angiogenesis. J Pathol (2001) 193:147-54. doi:10.1002/1096-9896(2000)
124. Achen MG, McColl BK, Stacker SA. Focus on lymphangiogenesis in tumor metastasis. Cancer Cell (2005) 7(2):121-7. doi:10.1016/j.ccr.2005.01.017
125. Salven P, Lymboussaki A, Heikkila P, Jaaskela-Saari H, Enholm B, Aase K, et al. Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. Am J Pathol (1998) 153:103-8. doi:10.1016/S0002-9440(10)65550-2
126. Griffioen AW. Anti-angiogenesis: making the tumor vulnerable to the immune system. Cancer Immunol Immunother (2008) 57(10):1553-8. doi:10.1007/s00262-008-0524-3
127. Hansen TF, Christensen R, Andersen RF, Sorensen FB, Johnsson A, Jakobsen A. MicroRNA-126 and epidermal growth factor-like domain 7-an angiogenic couple of importance in metastatic colorectal cancer. Results from the Nordic ACT trial. Br J Cancer (2013) 109(5):1243-51. doi:10.1038/bjc.2013.448
128. Delfortrie S, Pinte S, Mattot V, Samson C, Villain G, Caetano B, et al. Egfl7 promotes tumor escape from immunity by repressing endothelial cell activation. Cancer Res (2011) 71(23):7176-86. doi:10.1158/0008-5472.CAN-11-1301
129. Rosano L, Spinella F, Bagnato A. Endothelin 1 in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer (2013) 13(9):637-51. doi:10.1038/nrc3546
130. Wulfing P, Kersting C, Tio J, Fischer RJ, Wulfing C, Poremba C, et al. Endothelin-1, endothelin-A-and endothelin-B-receptor expression is correlated with vascular endothelial growth factor expression and angiogenesis in breast cancer. Clin Cancer Res (2004) 10:2393-400. doi:10.1158/1078-0432.CCR-03-0115
131. Buckanovich RJ, Facciabene A, Kim S, Benencia F, Sasaroli D, Balint K, et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med (2008) 14(1):28-36. doi:10.1038/nm1699
132. Nakashima S, Sugita Y, Miyoshi H, Arakawa F, Muta H, Ishibashi Y, et al. Endothelin B receptor expression in malignant gliomas: the perivascular immune escape mechanism of gliomas. J Neurooncol (2016) 127(1):23-32. doi:10.1007/s11060-015-2017-5
133. Sugita Y, Terasaki M, Nakashima S, Ohshima K, Morioka M, Abe H. Perivascular microenvironment in primary central nervous system lymphomas: the role of chemokines and the endothelin B receptor. Brain Tumor Pathol (2015) 32(1):41-8. doi:10.1007/s10014-014-0206-0
134. Tanaka T, Sho M, Takayama T, Wakatsuki K, Matsumoto S, Migita K, et al. Endothelin B receptor expression correlates with tumour angiogenesis and prognosis in oesophageal squamous cell carcinoma. Br J Cancer (2014) 110(4):1027-33. doi:10.1038/bjc.2013.784
135. Karikoski M, Marttila-Ichihara F, Elima K, Rantakari P, Hollmen M, Kelkka T, et al. Clever-1/stabilin-1 controls cancer growth and metastasis. Clin Cancer Res (2014) 20(24):6452-64. doi:10.1158/1078-0432.CCR-14-1236
136. Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med (2014) 20(6):607-15. doi:10.1038/nm.3541
137. Kzhyshkowska J, Gratchev A, Goerdt S. Stabilin-1, a homeostatic scavenger receptor with multiple functions. J Cell Mol Med (2006) 10(3):635-49. doi:10.2755/jcmm010.003.08
138. Karikoski M, Irjala H, Maksimow M, Miiluniemi M, Granfors K, Hernesniemi S, et al. Clever-1/Stabilin-1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation. Eur J Immunol (2009) 39(12):3477-87. doi:10.1002/eji.200939896
139. Irjala H, Alanen K, Grenman R, Heikkila P, Joensuu H, Jalkanen S. Mannose receptor (MR) and common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 direct the binding of cancer cells to the lymph vessel endothelium. Cancer Res (2003) 63:4671-6.
140. Irjala H, Elima K, Johansson E, Merinen M, Kontula K, Alanen K, et al. The same endothelial receptor controls lymphocyte traffic both in vascular and lymphatic vessels. Eur J Immunol (2003) 33:815-24. doi:10.1002/eji.200323859
141. Palazon A, Aragones J, Morales-Kastresana A, de Landazuri MO, Melero I. Molecular pathways: hypoxia response in immune cells fighting or promoting cancer. Clin Cancer Res (2012) 18(5):1207-13. doi:10.1158/1078-0432.CCR-11-1591
142. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature (2011) 475(7355):226-30. doi:10.1038/nature10169
143. Yan M, Jene N, Byrne D, Millar EKA, O'Toole S, McNeil CM, et al. Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers. Breast Cancer Res (2011) 13:R47. doi:10.1186/bcr2869
144. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med (2014) 211(5):781-90. doi:10.1084/jem.20131916
145. Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med (2015) 212(2):139-48. doi:10.1084/jem.20140559
146. Bellone M, Calcinotto A. Ways to enhance lymphocyte trafficking into tumors and fitness of tumor infiltrating lymphocytes. Front Oncol (2013) 3:231. doi:10.3389/fonc.2013.00231
147. Jain RK. Normalization of the tumour vasculature: an emerging concept in antiangiogenic therapy. Science (2005) 307:58-62. doi:10.1126/science.1104819
148. Farnsworth RH, Lackmann M, Achen MG, Stacker SA. Vascular remodeling in cancer. Oncogene (2014) 33(27):3496-505. doi:10.1038/onc.2013.304
149. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov (2011) 10(6):417-27. doi:10.1038/nrd3455
150. Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol (2013) 31(17):2205-18. doi:10.1200/JCO.2012.46.3653
151. Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalisation by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res (2004) 64:3731-6. doi:10.1158/0008-5472.CAN-04-0074
152. Hahn C, Schwartz MA. Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol (2009) 10(1):53-62. doi:10.1038/nrm2596
153. Wragg JW, Durant S, McGettrick HM, Sample KM, Egginton S, Bicknell R. Shear stress regulated gene expression and angiogenesis in vascular endothelium. Microcirculation (2014) 21(4):290-300. doi:10.1111/micc.12119
154. Buchanan CF, Verbridge SS, Vlachos PP, Rylander MN. Flow shear stress regulates endothelial barrier function and expression of angiogenic factors in a 3D microfluidic tumor vascular model. Cell Adh Migr (2014) 8(5):517-24. doi:10.4161/19336918.2014.970001
155. Chiu JJ, Lee PL, Chen CN, Lee CI, Chang SF, Chen LJ, et al. Shear stress increases ICAM-1 and decreases VCAM-1 and E-selectin expressions induced by tumor necrosis factor-[alpha] in endothelial cells. Arterioscler Thromb Vasc Biol (2004) 24(1):73-9. doi:10.1161/01.ATV.0000106321.63667.24
156. Raza A, Franklin MJ, Dudek AZ. Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am J Hematol (2010) 85(8):593-8. doi:10.1002/ajh.21745
157. Jain RK, Booth MF. What brings pericytes to tumor vessels? J Clin Invest (2003) 112(8):1134-6. doi:10.1172/JCI20087
158. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest (2003) 111(9):1287-95. doi:10.1172/JCI17929
159. Ruan J, Luo M, Wang C, Fan L, Yang SN, Cardenas M, et al. Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes. Blood (2013) 121(26):5192-202. doi:10.1182/blood-2013-03-490763
160. Meng M, Zaorsky NG, Deng L, Wang HH, Chao J, Zhao L, et al. Pericytes: a double-edged sword in cancer therapy. Future Oncol (2015) 11(1):169-79. doi:10.2217/fon.14.123
161. Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol (2009) 10(3):165-77. doi:10.1038/nrm2639
162. Keskin D, Kim J, Cooke VG, Wu CC, Sugimoto H, Gu C, et al. Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep (2015) 10(7):1066-81. doi:10.1016/j.celrep.2015.01.035
163. Coleman RL, Broaddus RR, Bodurka DC, Wolf JK, Burke TW, Kavanagh JJ, et al. Phase II trial of imatinib mesylate in patients with recurrent platinum-and taxane-resistant epithelial ovarian and primary peritoneal cancers. Gynecol Oncol (2006) 101(1):126-31. doi:10.1016/j.ygyno.2005.09.041
164. Raymond E, Brandes AA, Dittrich C, Fumoleau P, Coudert B, Clement PM, et al. Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European organisation for research and treatment of cancer brain tumor group study. J Clin Oncol (2008) 26(28):4659-65. doi:10.1200/JCO.2008.16.9235
165. Hong J, Tobin NP, Rundqvist H, Li T, Lavergne M, Garcia-Ibanez Y, et al. Role of tumor pericytes in the recruitment of myeloid-derived suppressor cells. J Natl Cancer Inst (2015) 107(10):djv209. doi:10.1093/jnci/djv209
166. Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature (2008) 453(7193):410-4. doi:10.1038/nature06868
167. Manzur M, Hamzah J, Ganss R. Modulation of G protein signaling normalizes tumor vessels. Cancer Res (2009) 69(2):396-9. doi:10.1158/0008-5472.CAN-08-2842
168. Manzur M, Hamzah J, Ganss R. Modulation of the "blood-tumor" barrier improves immunotherapy. Cell Cycle (2008) 7(16):2452-5. doi:10.4161/cc.7.16.6451
169. Jain RK, Martin JD, Stylianopoulos T. The role of mechanical forces in tumor growth and therapy. Annu Rev Biomed Eng (2014) 16:321-46. doi:10.1146/annurev-bioeng-071813-105259
170. Senger DR, Perruzzi CA, Feder J, Dvorak HF. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res (1986) 46:5629-32.
171. Yeo K-T, Wang HH, Nagy JA, Sioussat TM, Ledbetter SR, Hoogewerf AJ, et al. Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions. Cancer Res (1993) 53:2912-8.
172. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoural T cells, recurrence and survival in epithelial ovarian cancer. N Engl J Med (2003) 348:203-13. doi:10.1056/NEJMoa020177
173. Ager A, May MJ. Understanding high endothelial venules: lessons for cancer immunology. Oncoimmunology (2015) 4(6):e1008791. doi:10.1080/2162402X.2015.1008791
174. Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ, et al. Human solid tumors contain high endothelial venules: association with T-and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res (2011) 71(17):5678-87. doi:10.1158/0008-5472.CAN-11-0431
175. Dieu-Nosjean MC, Goc J, Giraldo NA, Sautes-Fridman C, Fridman WH. Tertiary lymphoid structures in cancer and beyond. Trends Immunol (2014) 35(11):571-80. doi:10.1016/j.it.2014.09.006
176. Thompson ED, Enriquez HL, Fu YX, Engelhard VH. Tumor masses support naive T cell infiltration, activation and differentiation into effectors. J Exp Med (2010) 207:1791-804. doi:10.1084/jem.20092454
177. Peske JD, Thompson ED, Gemta L, Baylis RA, Fu YX, Engelhard VH. Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity. Nat Commun (2015) 6:7114. doi:10.1038/ncomms8114
178. Shields JD, Kourtis IC, Tomei AA, Roberts JM, Swartz MA. Induction of lymphoidlike stroma and immune escape by tumours that express the chemokine CCL21. Science (2010) 328:749-52. doi:10.1126/science.1185837
179. Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer (2014) 14(3):159-72. doi:10.1038/nrc3677
180. Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure-an obstacle in cancer therapy. Nat Rev Cancer (2004) 4(10):806-13. doi:10.1038/nrc1456
181. Swartz MA, Lund AW. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat Rev Cancer (2012) 12(3):210-9. doi:10.1038/nrc3186
182. Ng CP, Hinz B, Swartz MA. Insterstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J Cell Sci (2005) 118:4731-9. doi:10.1242/jcs
183. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limon P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol (2010) 10(8):554-67. doi:10.1038/nri2808
184. Lund AW, Duraes FV, Hirosue S, Raghavan VR, Nembrini C, Thomas SN, et al. VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. Cell Rep (2012) 1(3):191-9. doi:10.1016/j.celrep.2012.01.005
185. Friedlaender MH, Baer H. Immunologic tolerance: role of the regional lymph node. Science (1972) 176:312-4. doi:10.1126/science.176.4032.312
186. Card CM, Yu SS, Swartz MA. Emerging roles of lymphatic endothelium in regulating adaptive immunity. J Clin Invest (2014) 124(3):943-52. doi:10.1172/JCI73316
187. Liao S, von der Weid PY. Lymphatic system: an active pathway for immune protection. Semin Cell Dev Biol (2015) 38:83-9. doi:10.1016/j.semcdb.2014.11.012
188. Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ, Ruddell A, et al. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med (2010) 207(4):681-8. doi:10.1084/jem.20092465
189. Fletcher AL, Lukacs-Kornek V, Reynoso ED, Pinner SE, Bellemare-Pelletier A, Curry MS, et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med (2010) 207(4):689-97. doi:10.1084/jem.20092642
190. Tewalt EF, Cohen JN, Rouhani SJ, Guidi CJ, Qiao H, Fahl SP, et al. Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood (2012) 120(24):4772-82. doi:10.1182/blood-2012-04427013
191. Rouhani SJ, Eccles JD, Riccardi P, Peske JD, Tewalt EF, Cohen JN, et al. Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction. Nat Commun (2015) 6:6771. doi:10.1038/ncomms7771
192. Lukacs-Kornek V, Malhotra D, Fletcher AL, Acton SE, Elpek KG, Tayalia P, et al. Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat Immunol (2011) 12(11):1096-104. doi:10.1038/ni.2112
193. Podgrabinska S, Kamalu O, Mayer L, Shimaoka M, Snoeck H, Randolph GJ, et al. Inflamed lymphatic endothelium suppresses dendritic cell maturation and function via Mac-1/ICAM-1-dependent mechanism. J Immunol (2009) 183(3):1767-79. doi:10.4049/jimmunol.0802167
194. Norder M, Gutierrez MG, Zicari S, Cervi E, Caruso A, Guzman CA. Lymph node-derived lymphatic endothelial cells express functional costimulatory molecules and impair dendritic cell-induced allogenic T-cell proliferation. FASEB J (2012) 26(7):2835-46. doi:10.1096/fj.12-205278
195. Chin AR, Wang SE. Cancer tills the premetastatic field: mechanistic basis and clinical implications. Clin Cancer Res (2016) 22(15):1-9. doi:10.1158/1078-0432.CCR-16-0028
196. Pereira ER, Jones D, Jung K, Padera TP. The lymph node microenvironment and its role in the progression of metastatic cancer. Semin Cell Dev Biol (2015) 38:98-105. doi:10.1016/j.semcdb.2015.01.008
197. Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med (2005) 201(7):1089-99. doi:10.1084/jem.20041896
198. Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood (2007) 109:1010-7. doi:10.1182/blood-200605-021758
199. Farnsworth RH, Karnezis T, Shayan R, Matsumoto M, Nowell CJ, Achen MG, et al. A role for bone morphogenetic protein-4 in lymph node vascular remodeling and primary tumor growth. Cancer Res (2011) 71(20):6547-57. doi:10.1158/0008-5472.CAN-11-0200
200. Qian CN, Berghuis B, Tsarfaty G, Bruch M, Kort EJ, Ditlev J, et al. Preparing the "soil": the primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. Cancer Res (2006) 66(21):10365-76. doi:10.1158/0008-5472.CAN-06-2977
201. Carriere V, Colisson R, Jiguet-Jiglaire C, Bellard E, Bouche G, Al Saati T, et al. Cancer cells regulate lymphocyte recruitment and leukocyte-endothelium interactions in the tumor-draining lymph node. Cancer Res (2005) 65(24):11639-48. doi:10.1158/0008-5472.CAN-05-1190
202. Girard JP, Moussion C, Forster R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol (2012) 12(11):762-73. doi:10.1038/nri3298
203. Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D, Lejeune F, et al. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res (2004) 64:2865-73. doi:10.1158/0008-5472.CAN-03-3066
204. Preynat-Seauve O, Contassot E, Schuler P, Piguet V, French LE, Huard B. Extralymphatic tumors prepare draining lymph nodes to invasion via a T-cell cross-tolerance process. Cancer Res (2007) 67(10):5009-16. doi:10.1158/0008-5472.CAN-06-4494
205. Matsumoto M, Roufail S, Inder R, Caesar C, Karnezis T, Shayan R, et al. Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis. Clin Exp Metastasis (2013) 30(6):819-32. doi:10.1007/s10585-013-9581-x
206. Shayan R, Inder R, Karnezis T, Caesar C, Paavonen K, Ashton MW, et al. Tumor location and nature of lymphatic vessels are key determinants of cancer metastasis. Clin Exp Metastasis (2013) 30(3):345-56. doi:10.1007/s10585-012-9541-x
207. Mlecnik B, Bindea G, Kirilovsky A, Angell HK, Obenauf AC, Tosolini M, et al. The tumor microenvironment and Immunoscore are critical determinants of dissemination to distal metastasis. Sci Transl Med (2016) 8(327):327ra26. doi:10.1126/scitranslmed.aad6352
208. Lund AW, Wagner M, Fankhauser M, Steinskog ES, Broggi MA, Spranger S, et al. Lymphatic vessels regulate immune microenvironments in human and murine melanoma. J Clin Invest (2016) 126(9):3389-402. doi:10.1172/JCI79434
209. Carman CV, Martinelli R. T lymphocyte-endothelial interactions: emerging understanding of trafficking and antigen-specific immunity. Front Immunol (2015) 6:603. doi:10.3389/fimmu.2015.00603
210. Epperson DE, Pober JS. Antigen-presenting function of human endothelial cells. Direct activation of resting CD8 T cells. J Immunol (1994) 153:5402-12.
211. Rodig N, Ryan T, Allen JA, Pang H, Grabie N, Chernova T, et al. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol (2003) 33(11):3117-26. doi:10.1002/eji.200324270
212. Huang X, Bai X, Cao Y, Wu J, Huang M, Tang D, et al. Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion. J Exp Med (2010) 207(3):505-20. doi:10.1084/jem.20090397
213. Riesenberg R, Weiler C, Spring O, Eder M, Buchner A, Popp T, et al. Expression of indoleamine 2, 3-dioxygenase in tumor endothelial cells correlates with long-term survival of patients with renal cell carcinoma. Clin Cancer Res (2007) 13(23):6993-7002. doi:10.1158/1078-0432.CCR-07-0942
214. Zang X, Allison JP. The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res (2007) 13(18 Pt 1):5271-9. doi:10.1158/1078-0432.CCR-07-1030
215. Sica GL, Choi I, Zhu G, Tamada K, Wang S, Tamura H, et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity (2003) 18:849-61. doi:10.1016/S1074-7613(03)00152-3
216. Suh WK, Gajewska BU, Okada H, Gronski MA, Bertram EM, Dawicki W, et al. The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol (2003) 4(9):899-906. doi:10.1038/ni967
217. Zang X, Sullivan PS, Soslow RA, Waitz R, Reuter VE, Wilton A, et al. Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas. Mod Pathol (2010) 23(8):1104-12. doi:10.1038/modpathol.2010.95
218. Brunner A, Hinterholzer S, Riss P, Heinze G, Brustmann H. Immunoexpression of B7-H3 in endometrial cancer: relation to tumor T-cell infiltration and prognosis. Gynecol Oncol (2012) 124(1):105-11. doi:10.1016/j.ygyno.2011.09.012
219. Brustmann H, Igaz M, Eder C, Brunner A. Epithelial and tumor-associated endothelial expression of B7-H3 in cervical carcinoma: relation with CD8+ intraepithelial lymphocytes, FIGO stage, and phosphohistone H3 (PHH3) reactivity. Int J Gynecol Pathol (2015) 34(2):187-95. doi:10.1097/PGP.0000000000000116
220. Crispen PL, Sheinin Y, Roth TJ, Lohse CM, Kuntz SM, Frigola X, et al. Tumor cell and tumor vasculature expression of B7-H3 predict survival in clear cell renal cell carcinoma. Clin Cancer Res (2008) 14(16):5150-7. doi:10.1158/1078-0432.CCR-08-0536
221. Krambeck AE, Thompson RH, Dong H, Lohse CM, Park ES, Kuntz SM, et al. B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival. Proc Natl Acad Sci U S A (2006) 103(27):10391-6. doi:10.1073/pnas.0600937103
222. He YC, Halford MM, Achen MG, Stacker SA. Exploring the role of endothelium in the tumour response to anti-angiogenic therapy. Biochem Soc Trans (2014) 42(6):1569-75. doi:10.1042/BST20140173
223. Fontanella C, Ongaro E, Bolzonello S, Guardascione M, Fasola G, Aprile G. Clinical advances in the development of novel VEGFR2 inhibitors. Ann Transl Med (2014) 2(12):123. doi:10.3978/j.issn.2305-5839.2014.08.14
224. Solomon B, Binns D, Roselt P, Weibe LI, McArthur GA, Cullinane C, et al. Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging. Mol Cancer Ther (2005) 4(9):1417-22. doi:10.1158/1535-7163.MCT-05-0066
225. Solomon B, Hagekyriakou J, Trivett MK, Stacker SA, McArthur GA, Cullinane C. EGFR blockade with ZD1839 ("Iressa") potentiates the antitumor effects of single and multiple fractions of ionizing radiation in human A431 squamous cell carcinoma. Int J Radiat Oncol Biol Phys (2003) 55(3):713-23. doi:10.1016/S0360-3016(02)04357-2
226. Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet (2016) 388:518-29. doi:10.1016/S0140-6736(15)01088-0
227. Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J, Snuderl M, et al. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A (2013) 110(47):19059-64. doi:10.1073/pnas.1318022110
228. Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A (2003) 100(8):4712-7. doi:10.1073/pnas.0830997100
229. Yuan J, Zhou J, Dong Z, Tandon S, Kuk D, Panageas KS, et al. Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res (2014) 2(2):127-32. doi:10.1158/2326-6066.CIR-13-0163
230. Wu X, Giobbie-Hurder A, Liao X, Lawrence D, McDermott D, Zhou J, et al. VEGF neutralization plus CTLA-4 blockade alters soluble and cellular factors associated with enhancing lymphocyte infiltration and humoral recognition in melanoma. Cancer Immunol Res (2016) 4(10):858-68. doi:10.1158/2326-6066.CIR-16-0084
231. Achen MG, Mann GB, Stacker SA. Targeting lymphangiogenesis to prevent tumour metastasis. Br J Cancer (2006) 94(10):1355-60. doi:10.1038/sj.bjc.6603120
232. Rinderknecht M, Villa A, Ballmer-Hofer K, Neri D, Detmar M. Phage-derived fully human monoclonal antibody fragments to human vascular endothelial growth factor-C block its interaction with VEGF receptor-2 and 3. PLoS One (2010) 5(8):e11941. doi:10.1371/journal.pone.0011941
233. Achen MG, Roufail S, Domagala T, Catimel B, Nice EC, Geleick DM, et al. Monoclonal antibodies to vascular endothelial growth factor-D block its interactions with both VEGF receptor-2 and VEGF-receptor 3. Eur J Biochem (2000) 267:2505-15. doi:10.1046/j.1432-1327.2000.01257.x
234. Davydova N, Roufail S, Streltsov VA, Stacker SA, Achen MG. The VD1 neutralizing antibody to vascular endothelial growth factor-D: binding epitope and relationship to receptor binding. J Mol Biol (2011) 407(4):581-93. doi:10.1016/j.jmb.2011.02.009
235. Persaud K, Tille J, Liu M, Zhu Z, Jimenez X, Pereira DS, et al. Involvement of the VEGF receptor 3 in tubular morphogenesis demonstrated with a human anti-human VEGR-3 monoclonal antibody that antagonises receptor activation by VEGF-C. J Cell Sci (2004) 117:2745-56. doi:10.1242/jcs
236. Albuquerque RJ, Hayashi T, Cho WG, Kleinman ME, Dridi S, Takeda A, et al. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med (2009) 15(9):1023-30. doi:10.1038/nm.2018
237. Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ, et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med (2001) 7:199-205. doi:10.1038/84651
238. Kodera Y, Katanasaka Y, Kitamura Y, Tsuda H, Nishio K, Tamura T, et al. Sunitinib inhibits lymphatic endothelial cell functions and lymph node metastasis in a breast cancer model through inhibition of vascular endothelial growth factor receptor 3. Breast Cancer Res (2011) 13:R66. doi:10.1186/bcr2903