International Journal of Stem Cells

Korean Society for Stem Cell Research (한국줄기세포학회)
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Exploring the Molecular and Developmental Dynamics of Endothelial Cell Differentiation

  • Yu Jung Shin (Department of Bioengineering, University of Washington) ;
  • Jung Hyun Lee (Institute for Stem Cell and Regenerative Medicine, University of Washington)
  • Received : 2023.06.11
  • Accepted : 2023.09.05
  • Published : 2024.02.28
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Abstract

The development and differentiation of endothelial cells (ECs) are fundamental processes with significant implications for both health and disease. ECs, which are found in all organs and blood vessels, play a crucial role in facilitating nutrient and waste exchange and maintaining proper vessel function. Understanding the intricate signaling pathways involved in EC development holds great promise for enhancing vascularization, tissue engineering, and vascular regeneration. Hematopoietic stem cells originating from hemogenic ECs, give rise to diverse immune cell populations, and the interaction between ECs and immune cells is vital for maintaining vascular integrity and regulating immune responses. Dysregulation of vascular development pathways can lead to various diseases, including cancer, where tumor-specific ECs promote tumor growth through angiogenesis. Recent advancements in single-cell genomics and in vivo genetic labeling have shed light on EC development, plasticity, and heterogeneity, uncovering tissue-specific gene expression and crucial signaling pathways. This review explores the potential of ECs in various applications, presenting novel opportunities for advancing vascular medicine and treatment strategies.

Keywords

Acknowledgement

This work was supported by the Elsa U Pardee Foundation (to JHL), MCC patient gift fund (to JHL), and American Heart Association Predoctoral fellowship (AHA 23PRE1014179, to YJS).

References

  1. Qiu J, Hirschi KK. Endothelial cell development and its application to regenerative medicine. Circ Res 2019;125:489-501
  2. Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996;380:435-439
  3. Miquerol L, Langille BL, Nagy A. Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development 2000;127:3941-3946
  4. Lee S, Chen TT, Barber CL, et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell 2007;130:691-703
  5. Gale NW, Dominguez MG, Noguera I, et al. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci U S A 2004;101:15949-15954
  6. Hellstrom M, Phng LK, Hofmann JJ, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 2007;445:776-780
  7. Gerhardt H, Golding M, Fruttiger M, et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 2003;161:1163-1177
  8. Cao Y, Zhang X, Wang L, et al. PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension. Proc Natl Acad Sci U S A 2019;116:13394-13403
  9. De Bock K, Georgiadou M, Schoors S, et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 2013;154:651-663
  10. Stratman AN, Schwindt AE, Malotte KM, Davis GE. Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood 2010;116:4720-4730
  11. Stenzel D, Nye E, Nisancioglu M, Adams RH, Yamaguchi Y, Gerhardt H. Peripheral mural cell recruitment requires cell-autonomous heparan sulfate. Blood 2009;114:915-924
  12. Hellstrom M, Gerhardt H, Kalen M, et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 2001;153:543-553
  13. Eklund L, Kangas J, Saharinen P. Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems. Clin Sci (Lond) 2017;131:87-103
  14. Fukuhara S, Sako K, Minami T, et al. Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat Cell Biol 2008;10:513-526
  15. Brindle NP, Saharinen P, Alitalo K. Signaling and functions of angiopoietin-1 in vascular protection. Circ Res 2006;98:1014-1023
  16. Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov 2017;16:635-661
  17. Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci U S A 2002;99:11205-11210
  18. Liu ZJ, Shirakawa T, Li Y, et al. Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 2003;23:14-25
  19. Quillien A, Moore JC, Shin M, et al. Distinct Notch signaling outputs pattern the developing arterial system. Development 2014;141:1544-1552
  20. Coultas L, Nieuwenhuis E, Anderson GA, et al. Hedgehog regulates distinct vascular patterning events through VEGF-dependent and -independent mechanisms. Blood 2010;116:653-660
  21. Corada M, Nyqvist D, Orsenigo F, et al. The Wnt/beta-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling. Dev Cell 2010;18:938-949
  22. Wythe JD, Dang LT, Devine WP, et al. ETS factors regulate Vegf-dependent arterial specification. Dev Cell 2013;26:45-58
  23. Stalmans I, Ng YS, Rohan R, et al. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 2002;109:327-336
  24. Seo S, Kume T. Forkhead transcription factors, Foxc1 and Foxc2, are required for the morphogenesis of the cardiac outflow tract. Dev Biol 2006;296:421-436
  25. You LR, Lin FJ, Lee CT, DeMayo FJ, Tsai MJ, Tsai SY. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 2005;435:98-104
  26. le Noble F, Fleury V, Pries A, Corvol P, Eichmann A, Reneman RS. Control of arterial branching morphogenesis in embryogenesis: go with the flow. Cardiovasc Res 2005;65:619-628
  27. Peirce SM, Skalak TC. Microvascular remodeling: a complex continuum spanning angiogenesis to arteriogenesis. Microcirculation 2003;10:99-111
  28. Fang JS, Coon BG, Gillis N, et al. Shear-induced NotchCx37-p27 axis arrests endothelial cell cycle to enable arterial specification. Nat Commun 2017;8:2149 Erratum in: Nat Commun 2018;9:720
  29. Noseda M, Chang L, McLean G, et al. Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: role of p21Cip1 repression. Mol Cell Biol 2004;24:8813-8822
  30. Kao CY, Xu M, Wang L, et al. Elevated COUP-TFII expression in dopaminergic neurons accelerates the progression of Parkinson's disease through mitochondrial dysfunction. PLoS Genet 2020;16:e1008868
  31. Xie X, Tang K, Yu CT, Tsai SY, Tsai MJ. Regulatory potential of COUP-TFs in development: stem/progenitor cells. Semin Cell Dev Biol 2013;24:687-693
  32. Chavkin NW, Genet G, Poulet M, et al. Endothelial cell cycle state determines propensity for arterial-venous fate. Nat Commun 2022;13:5891
  33. Dzierzak E, Bigas A. Blood development: hematopoietic stem cell dependence and independence. Cell Stem Cell 2018;22:639-651
  34. Wu Y, Hirschi KK. Regulation of hemogenic endothelial cell development and function. Annu Rev Physiol 2021;83:17-37
  35. Godin I, Cumano A. The hare and the tortoise: an embryonic haematopoietic race. Nat Rev Immunol 2002;2:593-604
  36. Tober J, Koniski A, McGrath KE, et al. The megakaryocyte lineage originates from hemangioblast precursors and is an integral component both of primitive and of definitive hematopoiesis. Blood 2007;109:1433-1441
  37. Rekhtman N, Radparvar F, Evans T, Skoultchi AI. Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells. Genes Dev 1999;13:1398-1411
  38. Frame JM, Fegan KH, Conway SJ, McGrath KE, Palis J. Definitive hematopoiesis in the yolk sac emerges from Wntresponsive hemogenic endothelium independently of circulation and arterial identity. Stem Cells 2016;34:431-444
  39. Ghosn E, Yoshimoto M, Nakauchi H, Weissman IL, Herzenberg LA. Hematopoietic stem cell-independent hematopoiesis and the origins of innate-like B lymphocytes. Development 2019;146:dev170571
  40. Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010;330:841-845
  41. Perdiguero EG, Klapproth K, Schulz C, et al. The origin of tissue-resident macrophages: when an erythro-myeloid progenitor is an erythro-myeloid progenitor. Immunity 2015;43:1023-1024
  42. Sheng J, Ruedl C, Karjalainen K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity 2015;43:382-393
  43. Perdiguero EG, Geissmann F. The development and maintenance of resident macrophages. Nat Immunol 2016;17:2-8
  44. Lieu YK, Reddy EP. Conditional c-myb knockout in adult hematopoietic stem cells leads to loss of self-renewal due to impaired proliferation and accelerated differentiation. Proc Natl Acad Sci U S A 2009;106:21689-21694
  45. Motazedian A, Bruveris FF, Kumar SV, et al. Multipotent RAG1＋ progenitors emerge directly from haemogenic endothelium in human pluripotent stem cell-derived haematopoietic organoids. Nat Cell Biol 2020;22:60-73
  46. Kobayashi M, Shelley WC, Seo W, et al. Functional B-1 progenitor cells are present in the hematopoietic stem celldeficient embryo and depend on Cbfβ for their development. Proc Natl Acad Sci U S A 2014;111:12151-12156
  47. Gritz E, Hirschi KK. Specification and function of hemogenic endothelium during embryogenesis. Cell Mol Life Sci 2016;73:1547-1567
  48. Muller AM, Medvinsky A, Strouboulis J, Grosveld F, Dzierzak E. Development of hematopoietic stem cell activity in the mouse embryo. Immunity 1994;1:291-301
  49. de Bruijn MF, Speck NA, Peeters MC, Dzierzak E. Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. EMBO J 2000;19:2465-2474
  50. Taoudi S, Medvinsky A. Functional identification of the hematopoietic stem cell niche in the ventral domain of the embryonic dorsal aorta. Proc Natl Acad Sci U S A 2007;104:9399-9403
  51. Fadlullah MZH, Neo WH, Lie-A-Ling M, et al. Murine AGM single-cell profiling identifies a continuum of hemogenic endothelium differentiation marked by ACE. Blood 2022;139:343-356
  52. Gomes AM, Kurochkin I, Chang B, et al. Cooperative transcription factor induction mediates hemogenic reprogramming. Cell Rep 2018;25:2821-2835.e7
  53. Thambyrajah R, Patel R, Mazan M, et al. New insights into the regulation by RUNX1 and GFI1(s) proteins of the endothelial to hematopoietic transition generating primordial hematopoietic cells. Cell Cycle 2016;15:2108-2114
  54. Lancrin C, Mazan M, Stefanska M, et al. GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoietic commitment. Blood 2012;120:314-322
  55. Bonkhofer F, Rispoli R, Pinheiro P, et al. Blood stem cell-forming haemogenic endothelium in zebrafish derives from arterial endothelium. Nat Commun 2019;10:3577
  56. Zhou Y, Zhang Y, Chen B, et al. Overexpression of GATA2 enhances development and maintenance of human embryonic stem cell-derived hematopoietic stem cell-like progenitors. Stem Cell Reports 2019;13:31-47
  57. Abdelfattah A, Hughes-Davies A, Clayfield L, et al. Gata2 haploinsufficiency promotes proliferation and functional decline of hematopoietic stem cells with myeloid bias during aging. Blood Adv 2021;5:4285-4290
  58. Coskun S, Chao H, Vasavada H, et al. Development of the fetal bone marrow niche and regulation of HSC quiescence and homing ability by emerging osteolineage cells. Cell Rep 2014;9:581-590
  59. Braet F, Wisse E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp Hepatol 2002;1:1
  60. Kadry H, Noorani B, Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 2020;17:69
  61. Jambusaria A, Hong Z, Zhang L, et al. Endothelial heterogeneity across distinct vascular beds during homeostasis and inflammation. Elife 2020;9:e51413
  62. Schaum N, Lehallier B, Hahn O, et al. Ageing hallmarks exhibit organ-specific temporal signatures. Nature 2020;583:596-602
  63. Tabula Muris Consortium; Overall coordination; Logistical coordination; et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 2018;562:367-372
  64. Paik DT, Tian L, Williams IM, et al. Single-cell RNA sequencing unveils unique transcriptomic signatures of organ-specific endothelial cells. Circulation 2020;142:1848-1862
  65. Marcu R, Choi YJ, Xue J, et al. Human organ-specific endothelial cell heterogeneity. iScience 2018;4:20-35
  66. Kalucka J, de Rooij LPMH, Goveia J, et al. Single-cell transcriptome atlas of murine endothelial cells. Cell 2020;180:764-779.e20
  67. Barry DM, McMillan EA, Kunar B, et al. Molecular determinants of nephron vascular specialization in the kidney. Nat Commun 2019;10:5705
  68. Yang AC, Vest RT, Kern F, et al. A human brain vascular atlas reveals diverse mediators of Alzheimer's risk. Nature 2022;603:885-892
  69. Vanlandewijck M, He L, Mae MA, et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature 2018;554:475-480 Erratum in: Nature 2018;560:E3
  70. Inverso D, Shi J, Lee KH, et al. A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie-Wnt signaling axis in the liver. Dev Cell 2021;56:1677-1693.e10
  71. Sabbagh MF, Heng JS, Luo C, et al. Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells. Elife 2018;7:e36187
  72. Genet N, Genet G, Chavkin NW, et al. Connexin 43-mediated neurovascular interactions regulate neurogenesis in the adult brain subventricular zone. Cell Rep 2023;42:112371
  73. Gillich A, Zhang F, Farmer CG, et al. Capillary cell-type specialization in the alveolus. Nature 2020;586:785-789
  74. Godoy RS, Cober ND, Cook DP, et al. Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation. Elife 2023;12:e80900
  75. Hua Y, Vella G, Rambow F, et al. Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1＋ T lymphocyte niches through a feed-forward loop. Cancer Cell 2022;40:1600-1618.e10 Erratum in: Cancer Cell 2023;41:226
  76. De Smedt J, van Os EA, Talon I, et al. PU.1 drives specification of pluripotent stem cell-derived endothelial cells to LSEC-like cells. Cell Death Dis 2021;12:84
  77. Halpern KB, Shenhav R, Massalha H, et al. Paired-cell sequencing enables spatial gene expression mapping of liver endothelial cells. Nat Biotechnol 2018;36:962-970
  78. Levy S, Sutton G, Ng PC, et al. The diploid genome sequence of an individual human. PLoS Biol 2007;5:e254
  79. Dumas SJ, Meta E, Borri M, et al. Single-cell RNA sequencing reveals renal endothelium heterogeneity and metabolic adaptation to water deprivation. J Am Soc Nephrol 2020;31:118-138
  80. Takemoto M, He L, Norlin J, et al. Large-scale identification of genes implicated in kidney glomerulus development and function. EMBO J 2006;25:1160-1174
  81. Wee H, Oh HM, Jo JH, Jun CD. ICAM-1/LFA-1 interaction contributes to the induction of endothelial cell-cell separation: implication for enhanced leukocyte diapedesis. Exp Mol Med 2009;41:341-348
  82. Gerszten RE, Luscinskas FW, Ding HT, et al. Adhesion of memory lymphocytes to vascular cell adhesion molecule-1-transduced human vascular endothelial cells under simulated physiological flow conditions in vitro. Circ Res 1996; 79:1205-1215
  83. Amersfoort J, Eelen G, Carmeliet P. Immunomodulation by endothelial cells - partnering up with the immune system? Nat Rev Immunol 2022;22:576-588
  84. Wedgwood JF, Hatam L, Bonagura VR. Effect of interferon-gamma and tumor necrosis factor on the expression of class I and class II major histocompatibility molecules by cultured human umbilical vein endothelial cells. Cell Immunol 1988;111:1-9
  85. Limmer A, Ohl J, Kurts C, et al. Efficient presentation of exogenous antigen by liver endothelial cells to CD8＋ T cells results in antigen-specific T-cell tolerance. Nat Med 2000;6:1348-1354
  86. Zhao L, Li Z, Vong JSL, et al. Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain. Nat Commun 2020;11:4413
  87. Shin YJ, Evitts KM, Jin S, et al. Amyloid beta peptides (Aβ) from Alzheimer's disease neuronal secretome induce endothelial activation in a human cerebral microvessel model. Neurobiol Dis 2023;181:106125
  88. Nascimento NR, Lessa LM, Kerntopf MR, et al. Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide. Proc Natl Acad Sci U S A 2006;103:218-223
  89. Kaludercic N, Di Lisa F. Mitochondrial ROS formation in the pathogenesis of diabetic cardiomyopathy. Front Cardiovasc Med 2020;7:12
  90. Mota RI, Morgan SE, Bahnson EM. Diabetic vasculopathy: macro and microvascular injury. Curr Pathobiol Rep 2020;8:1-14
  91. Katakami N. Mechanism of development of atherosclerosis and cardiovascular disease in diabetes mellitus. J Atheroscler Thromb 2018;25:27-39
  92. Tacke F, Alvarez D, Kaplan TJ, et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 2007;117:185-194
  93. Li D, Mehta JL. Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1 mRNA and chemical inhibitors. Arterioscler Thromb Vasc Biol 2000;20:1116-1122
  94. Davidson A, Aranow C. Lupus nephritis: lessons from murine models. Nat Rev Rheumatol 2010;6:13-20
  95. Renaudineau Y, Grunebaum E, Krause I, et al. Anti-endothelial cell antibodies (AECA) in systemic sclerosis--increased sensitivity using different endothelial cell substrates and association with other autoantibodies. Autoimmunity 2001;33:171-179
  96. Lopez-Isac E, Acosta-Herrera M, Kerick M, et al. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways. Nat Commun 2019;10:4955
  97. Benyamine A, Magalon J, Sabatier F, et al. Natural killer cells exhibit a peculiar phenotypic profile in systemic sclerosis and are potent inducers of endothelial microparticles release. Front Immunol 2018;9:1665
  98. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186
  99. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998;92:735-745
  100. Brady J, Neal J, Sadakar N, Gasque P. Human endosialin (tumor endothelial marker 1) is abundantly expressed in highly malignant and invasive brain tumors. J Neuropathol Exp Neurol 2004;63:1274-1283
  101. Harjunpaa H, Llort Asens M, Guenther C, Fagerholm SC. Cell adhesion molecules and their roles and regulation in the immune and tumor microenvironment. Front Immunol 2019;10:1078
  102. St Croix B, Rago C, Velculescu V, et al. Genes expressed in human tumor endothelium. Science 2000;289:1197-1202
  103. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003;3:401-410
  104. Guo P, Hu B, Gu W, et al. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am J Pathol 2003;162:1083-1093
  105. Cao Y, Cao R, Hedlund EM. R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol Med (Berl) 2008;86:785-789
  106. Song M, Finley SD. ERK and Akt exhibit distinct signaling responses following stimulation by pro-angiogenic factors. Cell Commun Signal 2020;18:114
  107. Quintero-Fabian S, Arreola R, Becerril-Villanueva E, et al. Role of matrix metalloproteinases in angiogenesis and cancer. Front Oncol 2019;9:1370
  108. Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006;441:437-443
  109. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 2020;20:651-668
  110. Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumorinfiltrating immune cells and their therapeutic implications. Cell Mol Immunol 2020;17:807-821
  111. Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol 2022;19:254-267
  112. Johnson PC, Gainor JF, Sullivan RJ, Longo DL, Chabner B. Immune checkpoint inhibitors - the need for innovation. N Engl J Med 2023;388:1529-1532
  113. Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 2018;50:1-11
  114. Schaaf MB, Garg AD, Agostinis P. Defining the role of the tumor vasculature in antitumor immunity and immunotherapy. Cell Death Dis 2018;9:115
  115. Duru G, van Egmond M, Heemskerk N. A window of opportunity: targeting cancer endothelium to enhance immunotherapy. Front Immunol 2020;11:584723
  116. Griffioen AW, Damen CA, Blijham GH, Groenewegen G. Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood 1996;88:667-673
  117. Molon B, Ugel S, Del Pozzo F, et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 2011;208:1949-1962
  118. Motz GT, Santoro SP, Wang LP, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 2014;20:607-615
  119. Rodig N, Ryan T, Allen JA, et al. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8＋ T cell activation and cytolysis. Eur J Immunol 2003;33:3117-3126
  120. Lanitis E, Irving M, Coukos G. Targeting the tumor vasculature to enhance T cell activity. Curr Opin Immunol 2015;33:55-63
  121. Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med 2017;9:eaak9679