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Vascular Normalization, T Cell Trafficking and Anti-tumor Immunity

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Defects in T Cell Trafficking and Resistance to Cancer Immunotherapy

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 9))

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Abstract

Improved understanding of the role of the immune system to limit tumor establishment and progression has led to the development and refinement of targeted immunotherapies. Treatments, such as cancer vaccines, CAR T cells and immune checkpoint inhibitors, aim to activate and harness T cells against cancer. However, tumors induce pathological angiogenesis and, at the same time, condition the tumor blood vessels to form a tumor vascular network that is highly abnormal. As a consequence, activated tumor- and stroma-specific T cells may be impeded from penetrating into the tumor lesions, greatly obstructing the therapeutic efficacy of such therapies. Hence, approaches designed to normalize the tumor vasculature are essential to optimize the activity of effector T cells as well as alternate innate and adaptive immune effector cells. In this chapter, we discuss how T cell trafficking is blunted at the tumor blood vessel interface and how therapies that are effective in normalizing the tumor vasculature such as anti-VEGF, tyrosine kinase inhibitors and vaccines targeting tumor blood vessel-associated antigens, among others, can re-establish T cell infiltration into an inflammatory tumor microenvironment, leading to therapeutic benefits in the cancer setting.

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Abbreviations

αSMA:

α-Smooth muscle actin

ADAM:

A disintegrin and metalloproteinase

ACT:

Adoptive cell transfer

Ang:

Angiopoietin

CAR:

Chimeric antigen receptor

CTL:

Cytotoxic T lymphocyte

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

DLK1:

Delta-like homologue 1

DC:

Dendritic cell

ET:

Endothelin

ETBR:

Endothelin B receptor

ECM:

Extracellular matrix

FGF:

Fibroblast growth factor

FDA:

Food and Drug Administration

HUVEC:

Human umbilical vein endothelial cells

HIF:

Hypoxia inducible factor

IGF:

Insulin-like growth factor

ICAM-1:

Intercellular adhesion molecule-1

IFNγ:

Interferon-γ

IL:

Interleukin

LFA-1:

Lymphocyte function-associated antigen-1

MHC:

Major histocompatibility complex

MDSC:

Myeloid derived suppressor cell

NRP:

Neuropilin

NSCLC:

Non-small cell lung cancer

PDGF:

Platelet-derived growth factor

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed cell death protein ligand 1

PSGL-1:

P-selectin glycoprotein ligand 1

RTK:

Receptor-type tyrosine kinase

RGS-5:

Regulator of G-protein signaling-5

Treg:

Regulatory T cell

RCC:

Renal cell carcinoma

SCLC:

Small cell lung cancer

TCR:

T cell receptor

Th1:

T helper type 1

TGF:

Transforming growth factor

TBVA:

Tumor blood vessel-associated antigen

TEM1:

Tumor endothelial marker-1

TIL:

Tumor infiltrating lymphocyte

TME:

Tumor microenvironment

TNFα:

Tumor necrosis factor-α

TAM:

Tumor-associated macrophage

TKI:

Tyrosine kinase inhibitors

VCAM-1:

Vascular adhesion molecule-1

VEC:

Vascular endothelial cells

VEGF:

Vascular endothelial growth factor

VEGFR:

VEGF receptor

VLA-4:

Very late antigen-4

References

  1. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.

    Article  CAS  PubMed  Google Scholar 

  2. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25(18):2586–93.

    Article  PubMed  Google Scholar 

  3. Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105(1):93–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene. 2010;29(8):1093–102.

    Article  CAS  PubMed  Google Scholar 

  5. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3):203–13.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. Weigelin B, Krause M, Friedl P. Cytotoxic T lymphocyte migration and effector function in the tumor microenvironment. Immunol Lett. 2011;138(1):19–21.

    Article  CAS  PubMed  Google Scholar 

  8. Ostrand-Rosenberg S. CD4+ T lymphocytes: a critical component of antitumor immunity. Cancer Invest. 2005;23(5):413–9.

    CAS  PubMed  Google Scholar 

  9. Protti MP, Monte LD, Lullo GD. Tumor antigen-specific CD4+ T cells in cancer immunity: from antigen identification to tumor prognosis and development of therapeutic strategies. Tissue Antigens. 2014;83(4):237–46.

    Article  CAS  PubMed  Google Scholar 

  10. Butterfield LH. Dendritic cells in cancer immunotherapy clinical trials: are we making progress? Front Immunol. 2013;4:454.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012;12(4):269–81.

    Article  CAS  PubMed  Google Scholar 

  12. Duong CP, Westwood JA, Berry LJ, Darcy PK, Kershaw MH. Enhancing the specificity of T-cell cultures for adoptive immunotherapy of cancer. Immunotherapy. 2011;3(1):33–48.

    Article  CAS  PubMed  Google Scholar 

  13. McIlroy D, Gregoire M. Optimizing dendritic cell-based anticancer immunotherapy: maturation state does have clinical impact. Cancer Immunol Immunother. 2003;52(10):583–91.

    Article  PubMed  Google Scholar 

  14. Zhong S, Malecek K, Johnson LA, Yu Z, Vega-Saenz de Miera E, Darvishian F, McGary K, Huang K, Boyer J, Corse E, Shao Y, Rosenberg SA, Restifo NP, Osman I, Krogsgaard M. T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy. Proc Natl Acad Sci U S A. 2013;110(17):6973–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wojtowicz-Praga S. Reversal of tumor-induced immunosuppression: a new approach to cancer therapy. J Immunother. 1997;20(3):165–77.

    Article  CAS  PubMed  Google Scholar 

  16. Leone P, Shin EC, Perosa F, Vacca A, Dammacco F, Racanelli V. MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J Natl Cancer Inst. 2013;105(16):1172–87.

    Article  CAS  PubMed  Google Scholar 

  17. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4(5):336–47.

    Article  CAS  PubMed  Google Scholar 

  18. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800.

    CAS  PubMed  Google Scholar 

  19. Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 2014;6(3):1670–90.

    Article  CAS  Google Scholar 

  21. Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ. The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology. 2013;138(2):105–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. von Andrian UH, Mackay CR. T-cell function and migration. Two sides of the same coin. N Engl J Med. 2000;343(14):1020–34.

    Article  Google Scholar 

  23. Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol. 1993;11:767–804.

    Article  CAS  PubMed  Google Scholar 

  24. Nolz JC. Naive, effector and memory CD8 T-cell trafficking: parallels and distinctions. Immunotherapy. 2011;3(10):1223–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Eelen G, de Zeeuw P, Simons M, Carmeliet P. Endothelial cell metabolism in normal and diseased vasculature. Circ Res. 2015;116(7):1231–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Michiels C. Endothelial cell functions. J Cell Physiol. 2003;196(3):430–43.

    Article  CAS  PubMed  Google Scholar 

  27. Armulik A, Genove G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 2011;21(2):193–215.

    Article  CAS  PubMed  Google Scholar 

  28. Gerhardt H, Betsholtz C. Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. 2003;314(1):15–23.

    Article  PubMed  Google Scholar 

  29. von Tell D, Armulik A, Betsholtz C. Pericytes and vascular stability. Exp Cell Res. 2006;312(5):623–9.

    Article  CAS  Google Scholar 

  30. Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer. 2003;3(6):422–33.

    Article  CAS  PubMed  Google Scholar 

  31. Form DM, Pratt BM, Madri JA. Endothelial cell proliferation during angiogenesis. In vitro modulation by basement membrane components. Lab Invest. 1986;55(5):521–30.

    CAS  PubMed  Google Scholar 

  32. Bottos A, Bardelli A. Oncogenes and angiogenesis: a way to personalize anti-angiogenic therapy? Cell Mol Life Sci. 2013;70(21):4131–40.

    Article  CAS  PubMed  Google Scholar 

  33. Dor Y, Porat R, Keshet E. Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. Am J Physiol Cell Physiol. 2001;280(6):C1367–74.

    CAS  PubMed  Google Scholar 

  34. Ferrara N, Mass RD, Campa C, Kim R. Targeting VEGF-A to treat cancer and age-related macular degeneration. Annu Rev Med. 2007;58:491–504.

    Article  CAS  PubMed  Google Scholar 

  35. Sakurai T, Kudo M. Signaling pathways governing tumor angiogenesis. Oncology. 2011;81 Suppl 1:24–9.

    Article  CAS  PubMed  Google Scholar 

  36. Plate KH, Scholz A, Dumont DJ. Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited. Acta Neuropathol. 2012;124(6):763–75.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Bates D, Hillman N, Williams B, Neal C, Pocock T. Regulation of microvascular permeability by vascular endothelial growth factors. J Anat. 2002;200(6):581–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science. 1999;284(5422):1994–8.

    Article  CAS  PubMed  Google Scholar 

  39. Cross MJ, Claesson-Welsh L. FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci. 2001;22(4):201–7.

    Article  CAS  PubMed  Google Scholar 

  40. Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol. 2005;7(4):452–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2002;160(3):985–1000.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2003;163(5):1801–15.

    Article  PubMed  PubMed Central  Google Scholar 

  43. McDonald DM, Choyke PL. Imaging of angiogenesis: from microscope to clinic. Nat Med. 2003;9(6):713–25.

    Article  CAS  PubMed  Google Scholar 

  44. Claesson-Welsh L. Blood vessels as targets in tumor therapy. Ups J Med Sci. 2012;117(2):178–86.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol. 2000;156(4):1363–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jain RK, Munn LL, Fukumura D. Dissecting tumour pathophysiology using intravital microscopy. Nat Rev Cancer. 2002;2(4):266–76.

    Article  CAS  PubMed  Google Scholar 

  47. Ariffin AB, Forde PF, Jahangeer S, Soden DM, Hinchion J. Releasing pressure in tumors: what do we know so far and where do we go from here? A review. Cancer Res. 2014;74(10):2655–62.

    Article  CAS  PubMed  Google Scholar 

  48. Lunt SJ, Fyles A, Hill RP, Milosevic M. Interstitial fluid pressure in tumors: therapeutic barrier and biomarker of angiogenesis. Future Oncol. 2008;4(6):793–802.

    Article  PubMed  Google Scholar 

  49. Bellone M, Calcinotto A. Ways to enhance lymphocyte trafficking into tumors and fitness of tumor infiltrating lymphocytes. Front Oncol. 2013;3:231.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Palazon A, Goldrath AW, Nizet V, Johnson RS. HIF transcription factors, inflammation, and immunity. Immunity. 2014;41(4):518–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hoskin DW, Mader JS, Furlong SJ, Conrad DM, Blay J. Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells (review). Int J Oncology. 2008;32(3):527–35.

    CAS  Google Scholar 

  52. Siemens DR, Hu N, Sheikhi AK, Chung E, Frederiksen LJ, Pross H, Graham CH. Hypoxia increases tumor cell shedding of MHC class I chain-related molecule: role of nitric oxide. Cancer Res. 2008;68(12):4746–53.

    Article  CAS  PubMed  Google Scholar 

  53. Barsoum IB, Hamilton TK, Li X, Cotechini T, Miles EA, Siemens DR, Graham CH. Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: role of nitric oxide. Cancer Res. 2011;71(24):7433–41.

    Article  CAS  PubMed  Google Scholar 

  54. Chitadze G, Lettau M, Bhat J, Wesch D, Steinle A, Furst D, Mytilineos J, Kalthoff H, Janssen O, Oberg HH, Kabelitz D. Shedding of endogenous MHC class I-related chain molecules A and B from different human tumor entities: heterogeneous involvement of the “a disintegrin and metalloproteases” 10 and 17. Int J Cancer. 2013;133(7):1557–66.

    Article  CAS  PubMed  Google Scholar 

  55. Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 2014;74(3):665–74.

    Article  CAS  PubMed  Google Scholar 

  56. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, Johnson RS, Goldrath AW. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol. 2013;14(11):1173–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kumar V, Gabrilovich DI. Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology. 2014;143(4):512–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Alexander MR, Owens GK. Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. Annu Rev Physiol. 2012;74:13–40.

    Article  CAS  PubMed  Google Scholar 

  59. Ghilardi C, Chiorino G, Dossi R, Nagy Z, Giavazzi R, Bani M. Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium. BMC Genomics. 2008;9:201.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Schaer DA, Lesokhin AM, Wolchok JD. Hiding the road signs that lead to tumor immunity. J Exp Med. 2011;208(10):1937–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ruoslahti E. Specialization of tumour vasculature. Nat Rev Cancer. 2002;2(2):83–90.

    Article  PubMed  Google Scholar 

  62. Schwartz JD, Rowinsky EK, Youssoufian H, Pytowski B, Wu Y. Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18 F1 (Human antibody targeting vascular endothelial growth factor receptor-1). Cancer. 2010;116(4 Suppl):1027–32.

    Article  CAS  PubMed  Google Scholar 

  63. Smith NR, Baker D, James NH, Ratcliffe K, Jenkins M, Ashton SE, Sproat G, Swann R, Gray N, Ryan A, Jurgensmeier JM, Womack C. Vascular endothelial growth factor receptors VEGFR-2 and VEGFR-3 are localized primarily to the vasculature in human primary solid cancers. Clin Cancer Res. 2010;16(14):3548–61.

    Article  CAS  PubMed  Google Scholar 

  64. Bouzin C, Brouet A, De Vriese J, Dewever J, Feron O. Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: identification of caveolin-1 and nitric oxide as control points of endothelial cell energy. J Immunol. 2007;178(3):1505–11.

    Article  CAS  PubMed  Google Scholar 

  65. Xin Y, Li J, Wu J, Kinard R, Weekes CD, Patnaik A, Lorusso P, Brachmann R, Tong RK, Yan Y, Watts R, Bai S, Hegde PS. Pharmacokinetic and pharmacodynamic analysis of circulating biomarkers of anti-NRP1, a novel antiangiogenesis agent, in two phase I trials in patients with advanced solid tumors. Clin Cancer Res. 2012;18(21):6040–8.

    Article  CAS  PubMed  Google Scholar 

  66. Ben Q, Zheng J, Fei J, An W, Li P, Li Z, Yuan Y. High neuropilin 1 expression was associated with angiogenesis and poor overall survival in resected pancreatic ductal adenocarcinoma. Pancreas. 2014;43(5):744–9.

    Article  CAS  PubMed  Google Scholar 

  67. Cheng W, Fu D, Wei ZF, Xu F, Xu XF, Liu YH, Ge JP, Tian F, Han CH, Zhang ZY, Zhou LM. NRP-1 expression in bladder cancer and its implications for tumor progression. Tumour Biol. 2014;35(6):6089–94.

    Article  CAS  PubMed  Google Scholar 

  68. Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, Chung YC, Wu MH, Yang SC, Pan SH, Shih JY, Chan WK, Yang PC. Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res. 2007;13(16):4759–68.

    Article  CAS  PubMed  Google Scholar 

  69. Zhu H, Cai H, Tang M, Tang J. Neuropilin-1 is overexpressed in osteosarcoma and contributes to tumor progression and poor prognosis. Clin Transl Oncol. 2014;16(8):732–8.

    Article  CAS  PubMed  Google Scholar 

  70. Geretti E, Klagsbrun M. Neuropilins: novel targets for anti-angiogenesis therapies. Cell Adh Migr. 2007;1(2):56–61.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Nanda A, St Croix B. Tumor endothelial markers: new targets for cancer therapy. Curr Opin Oncol. 2004;16(1):44–9.

    Article  CAS  PubMed  Google Scholar 

  72. Otsubo T, Hida Y, Ohga N, Sato H, Kai T, Matsuki Y, Takasu H, Akiyama K, Maishi N, Kawamoto T, Shinohara N, Nonomura K, Hida K. Identification of novel targets for antiangiogenic therapy by comparing the gene expressions of tumor and normal endothelial cells. Cancer Sci. 2014;105(5):560–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Buckanovich RJ, Facciabene A, Kim S, Benencia F, Sasaroli D, Balint K, Katsaros D, O’Brien-Jenkins A, Gimotty PA, Coukos G. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med. 2008;14(1):28–36.

    Article  CAS  PubMed  Google Scholar 

  74. Bagnato A, Spinella F. Emerging role of endothelin-1 in tumor angiogenesis. Trends Endocrinol Metab. 2003;14(1):44–50.

    Article  CAS  PubMed  Google Scholar 

  75. Rosano L, Spinella F, Bagnato A. Endothelin 1 in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2013;13(9):637–51.

    Article  CAS  PubMed  Google Scholar 

  76. Bagnato A, Spinella F, Rosano L. Emerging role of the endothelin axis in ovarian tumor progression. Endocr Relat Cancer. 2005;12(4):761–72.

    Article  CAS  PubMed  Google Scholar 

  77. Tsukahara H, Ende H, Magazine HI, Bahou WF, Goligorsky MS. Molecular and functional characterization of the non-isopeptide-selective ETB receptor in endothelial cells. Receptor coupling to nitric oxide synthase. J Biol Chem. 1994;269(34):21778–85.

    CAS  PubMed  Google Scholar 

  78. Berger M, Bergers G, Arnold B, Hammerling GJ, Ganss R. Regulator of G-protein signaling-5 induction in pericytes coincides with active vessel remodeling during neovascularization. Blood. 2005;105(3):1094–101.

    Article  CAS  PubMed  Google Scholar 

  79. Manzur M, Ganss R. Regulator of G protein signaling 5: a new player in vascular remodeling. Trends Cardiovasc Med. 2009;19(1):26–30.

    Article  CAS  PubMed  Google Scholar 

  80. Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Grone HJ, Hammerling GJ, Arnold B, Ganss R. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature. 2008;453(7193):410–4.

    Article  CAS  PubMed  Google Scholar 

  81. Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007;6(4):273–86.

    Article  CAS  PubMed  Google Scholar 

  82. Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013;31(17):2205–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Shojaei F. Anti-angiogenesis therapy in cancer: current challenges and future perspectives. Cancer Lett. 2012;320(2):130–7.

    Article  CAS  PubMed  Google Scholar 

  84. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58–62.

    Article  CAS  PubMed  Google Scholar 

  85. Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz de Almodovar C, De Smet F, Vinckier S, Aragones J, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell. 2009;136(5):839–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Curnis F, Sacchi A, Borgna L, Magni F, Gasparri A, Corti A. Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13). Nat Biotechnol. 2000;18(11):1185–90.

    Article  CAS  PubMed  Google Scholar 

  87. Bellone M, Calcinotto A, Corti A. Won’t you come on in? How to favor lymphocyte infiltration in tumors. Oncoimmunology. 2012;1(6):986–8.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Lorusso D, Scambia G, Amadio G, di Legge A, Pietragalla A, De Vincenzo R, Masciullo V, Di Stefano M, Mangili G, Citterio G, Mantori M, Lambiase A, Bordignon C. Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients. Br J Cancer. 2012;107(1):37–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4(6):423–36.

    Article  CAS  PubMed  Google Scholar 

  90. Maiti R. Metronomic chemotherapy. J Pharmacol Pharmacother. 2014;5(3):186–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pasquier E, Kavallaris M, Andre N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol. 2010;7(8):455–65.

    Article  PubMed  Google Scholar 

  92. Hermans IF, Chong TW, Palmowski MJ, Harris AL, Cerundolo V. Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer Res. 2003;63(23):8408–13.

    CAS  PubMed  Google Scholar 

  93. Chen G, Emens LA. Chemoimmunotherapy: reengineering tumor immunity. Cancer Immunol Immunother. 2013;62(2):203–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. De Vita S, De Matteis S, Laurenti L, Chiusolo P, Reddiconto G, Fiorini A, Leone G, Sica S. Secondary Ph + acute lymphoblastic leukemia after temozolomide. Ann Hematol. 2005;84(11):760–2.

    Article  PubMed  Google Scholar 

  95. Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57(20):4593–9.

    CAS  PubMed  Google Scholar 

  96. Ciombor KK, Berlin J, Chan E. Aflibercept. Clin Cancer Res. 2013;19(8):1920–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Byrne AT, Ross L, Holash J, Nakanishi M, Hu L, Hofmann JI, Yancopoulos GD, Jaffe RB. Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res. 2003;9(15):5721–8.

    CAS  PubMed  Google Scholar 

  98. Rosen LS. VEGF-targeted therapy: therapeutic potential and recent advances. Oncologist. 2005;10(6):382–91.

    Article  CAS  PubMed  Google Scholar 

  99. Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther. 2006;28(11):1779–802.

    Article  CAS  PubMed  Google Scholar 

  100. Verheul HM, Hammers H, van Erp K, Wei Y, Sanni T, Salumbides B, Qian DZ, Yancopoulos GD, Pili R. Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model. Clin Cancer Res. 2007;13(14):4201–8.

    Article  CAS  PubMed  Google Scholar 

  101. Ma J, Waxman DJ. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Mol Cancer Ther. 2008;7(12):3670–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tejpar S, Prenen H, Mazzone M. Overcoming resistance to antiangiogenic therapies. Oncologist. 2012;17(8):1039–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. De Falco S. Antiangiogenesis therapy: an update after the first decade. Korean J Intern Med. 2014;29(1):1–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hojjat-Farsangi M. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Int J Mol Sci. 2014;15(8):13768–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Dabney R, Devine R, Sein N, George B. New agents in renal cell carcinoma. Target Oncol. 2014;9(3):183–93.

    Article  PubMed  Google Scholar 

  107. Iyer R, Fetterly G, Lugade A, Thanavala Y. Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010;11(11):1943–55.

    Article  CAS  PubMed  Google Scholar 

  108. Nguewa PA, Calvo A, Pullamsetti SS, Banat GA, Grimminger F, Savai R. Tyrosine kinase inhibitors with antiangiogenic properties for the treatment of non-small cell lung cancer. Expert Opin Investig Drugs. 2011;20(1):61–74.

    Article  CAS  PubMed  Google Scholar 

  109. Sonpavde G, Hutson TE, Sternberg CN. Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opin Investig Drugs. 2008;17(2):253–61.

    Article  CAS  PubMed  Google Scholar 

  110. Harris PA, Boloor A, Cheung M, Kumar R, Crosby RM, Davis-Ward RG, Epperly AH, Hinkle KW, Hunter 3rd RN, Johnson JH, Knick VB, Laudeman CP, Luttrell DK, Mook RA, Nolte RT, Rudolph SK, Szewczyk JR, Truesdale AT, Veal JM, Wang L, Stafford JA. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-b enzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem. 2008;51(15):4632–40.

    Article  CAS  PubMed  Google Scholar 

  111. Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, Chen JH, Rewolinski DA, Yamazaki S, Wu EY, McTigue MA, Murray BW, Kania RS, O’Connor P, Shalinsky DR, Bender SL. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008;14(22):7272–83.

    Article  CAS  PubMed  Google Scholar 

  112. Huang D, Ding Y, Li Y, Luo WM, Zhang ZF, Snider J, Vandenbeldt K, Qian CN, Teh BT. Sunitinib acts primarily on tumor endothelium rather than tumor cells to inhibit the growth of renal cell carcinoma. Cancer Res. 2010;70(3):1053–62.

    Article  CAS  PubMed  Google Scholar 

  113. Mangiameli DP, Blansfield JA, Kachala S, Lorang D, Schafer PH, Muller GW, Stirling DI, Libutti SK. Combination therapy targeting the tumor microenvironment is effective in a model of human ocular melanoma. J Transl Med. 2007;5:38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Hamberg P, Verweij J, Sleijfer S. (Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor. Oncologist. 2010;15(6):539–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9(1):327–37.

    CAS  PubMed  Google Scholar 

  116. O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, Wong LM, Hong W, Lee LB, Town A, Smolich BD, Manning WC, Murray LJ, Heinrich MC, Cherrington JM. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003;101(9):3597–605.

    Article  PubMed  CAS  Google Scholar 

  117. Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, Schwartz M, Divino CM, Pan PY, Chen SH. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bose A, Taylor JL, Alber S, Watkins SC, Garcia JA, Rini BI, Ko JS, Cohen PA, Finke JH, Storkus WJ. Sunitinib facilitates the activation and recruitment of therapeutic anti-tumor immunity in concert with specific vaccination. Int J Cancer. 2011;129(9):2158–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ko JS, Rayman P, Ireland J, Swaidani S, Li G, Bunting KD, Rini B, Finke JH, Cohen PA. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res. 2010;70(9):3526–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Finke JH, Rini B, Ireland J, Rayman P, Richmond A, Golshayan A, Wood L, Elson P, Garcia J, Dreicer R, Bukowski R. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res. 2008;14(20):6674–82.

    Article  CAS  PubMed  Google Scholar 

  121. Gu Y, Zhao W, Meng F, Qu B, Zhu X, Sun Y, Shu Y, Xu Q. Sunitinib impairs the proliferation and function of human peripheral T cell and prevents T-cell-mediated immune response in mice. Clin Immunol. 2010;135(1):55–62.

    Article  CAS  PubMed  Google Scholar 

  122. Alfaro C, Suarez N, Gonzalez A, Solano S, Erro L, Dubrot J, Palazon A, Hervas-Stubbs S, Gurpide A, Lopez-Picazo JM, Grande-Pulido E, Melero I, Perez-Gracia JL. Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes. Br J Cancer. 2009;100(7):1111–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kim S, Ding W, Zhang L, Tian W, Chen S. Clinical response to sunitinib as a multitargeted tyrosine-kinase inhibitor (TKI) in solid cancers: a review of clinical trials. Onco Targets Ther. 2014;7:719–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Vinik AI, Raymond E. Pancreatic neuroendocrine tumors: approach to treatment with focus on sunitinib. Therap Adv Gastroenterol. 2013;6(5):396–411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ibrahim N, Yu Y, Walsh WR, Yang JL. Molecular targeted therapies for cancer: sorafenib mono-therapy and its combination with other therapies (review). Oncol Rep. 2012;27(5):1303–11.

    CAS  PubMed  Google Scholar 

  126. Thomas L, Lai SY, Dong W, Feng L, Dadu R, Regone RM, Cabanillas ME. Sorafenib in metastatic thyroid cancer: a systematic review. Oncologist. 2014;19(3):251–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Deeks ED. Pazopanib: in advanced soft tissue sarcoma. Drugs. 2012;72(16):2129–40.

    Article  CAS  PubMed  Google Scholar 

  128. Drabkin HA. Pazopanib and anti-VEGF therapy. Open Access J Urol. 2010;2:35–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Cheever MA, Higano CS. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res. 2011;17(11):3520–6.

    Article  PubMed  Google Scholar 

  130. Dong Y, Qian J, Ibrahim R, Berzofsky JA, Khleif SN. Identification of H-2Db-specific CD8+ T-cell epitopes from mouse VEGFR2 that can inhibit angiogenesis and tumor growth. J Immunother. 2006;29(1):32–40.

    Article  CAS  PubMed  Google Scholar 

  131. Ishizaki H, Tsunoda T, Wada S, Yamauchi M, Shibuya M, Tahara H. Inhibition of tumor growth with antiangiogenic cancer vaccine using epitope peptides derived from human vascular endothelial growth factor receptor 1. Clin Cancer Res. 2006;12(19):5841–9.

    Article  CAS  PubMed  Google Scholar 

  132. Wada S, Tsunoda T, Baba T, Primus FJ, Kuwano H, Shibuya M, Tahara H. Rationale for antiangiogenic cancer therapy with vaccination using epitope peptides derived from human vascular endothelial growth factor receptor 2. Cancer Res. 2005;65(11):4939–46.

    Article  CAS  PubMed  Google Scholar 

  133. Yamaue H, Tsunoda T, Tani M, Miyazawa M, Yamao K, Mizuno N, Okusaka T, Ueno H, Boku N, Fukutomi A, Ishii H, Ohkawa S, Furukawa M, Maguchi H, Ikeda M, Togashi Y, Nishio K, Ohashi Y. Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer. PEGASUS-PC Study Cancer Sci. 2015;106(7):883–90.

    Article  CAS  PubMed  Google Scholar 

  134. Hazama S, Nakamura Y, Takenouchi H, Suzuki N, Tsunedomi R, Inoue Y, Tokuhisa Y, Iizuka N, Yoshino S, Takeda K, Shinozaki H, Kamiya A, Furukawa H, Oka M. A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer; safety, immunological response, and clinical outcome. J Transl Med. 2014;12:63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Okamoto I, Arao T, Miyazaki M, Satoh T, Okamoto K, Tsunoda T, Nishio K, Nakagawa K. Clinical phase I study of elpamotide, a peptide vaccine for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors. Cancer Sci. 2012;103(12):2135–8.

    Article  CAS  PubMed  Google Scholar 

  136. Okuyama R, Aruga A, Hatori T, Takeda K, Yamamoto M. Immunological responses to a multi-peptide vaccine targeting cancer-testis antigens and VEGFRs in advanced pancreatic cancer patients. Oncoimmunology. 2013;2(11), e27010.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Suzuki H, Fukuhara M, Yamaura T, Mutoh S, Okabe N, Yaginuma H, Hasegawa T, Yonechi A, Osugi J, Hoshino M, Kimura T, Higuchi M, Shio Y, Ise K, Takeda K, Gotoh M. Multiple therapeutic peptide vaccines consisting of combined novel cancer testis antigens and anti-angiogenic peptides for patients with non-small cell lung cancer. J Transl Med. 2013;11:97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Zhao X, Bose A, Komita H, Taylor JL, Chi N, Lowe DB, Okada H, Cao Y, Mukhopadhyay D, Cohen PA, Storkus WJ. Vaccines targeting tumor blood vessel antigens promote CD8(+) T cell-dependent tumor eradication or dormancy in HLA-A2 transgenic mice. J Immunol. 2012;188(4):1782–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Chi Sabins N, Taylor JL, Fabian KP, Appleman LJ, Maranchie JK, Stolz DB, Storkus WJ. DLK1: a novel target for immunotherapeutic remodeling of the tumor blood vasculature. Mol Ther. 2013;21(10):1958–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Facciponte JG, Ugel S, De Sanctis F, Li C, Wang L, Nair G, Sehgal S, Raj A, Matthaiou E, Coukos G, Facciabene A. Tumor endothelial marker 1-specific DNA vaccination targets tumor vasculature. J Clin Invest. 2014;124(4):1497–511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Sharpe M, Mount N. Genetically modified T cells in cancer therapy: opportunities and challenges. Dis Model Mech. 2015;8(4):337–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Fu X, Rivera A, Tao L, Zhang X. Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors, and increase nanoparticle delivery. Int J Cancer. 2013;133(10):2483–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Chinnasamy D, Yu Z, Kerkar SP, Zhang L, Morgan RA, Restifo NP, Rosenberg SA. Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin Cancer Res. 2012;18(6):1672–83.

    Article  CAS  PubMed  Google Scholar 

  145. Vujanovic L, Butterfield LH. Melanoma cancer vaccines and anti-tumor T cell responses. J Cell Biochem. 2007;102(2):301–10.

    Article  CAS  PubMed  Google Scholar 

  146. Yu Z, Restifo NP. Cancer vaccines: progress reveals new complexities. J Clin Invest. 2002;110(3):289–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 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.

    Article  PubMed  CAS  Google Scholar 

  148. Griffioen AW, Weiss A, Berndsen RH, Abdul UK, te Winkel MT, Nowak-Sliwinska P. The emerging quest for the optimal angiostatic combination therapy. Biochem Soc Trans. 2014;42(6):1608–15.

    Article  CAS  PubMed  Google Scholar 

  149. Bose A, Lowe DB, Rao A, Storkus WJ. Combined vaccine + axitinib therapy yields superior antitumor efficacy in a murine melanoma model. Melanoma Res. 2012;22(3):236–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Lowe DB, Bose A, Taylor JL, Tawbi H, Lin Y, Kirkwood JM, Storkus WJ. Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma. Oncoimmunology. 2014;3(1), e27589.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Farsaci B, Higgins JP, Hodge JW. Consequence of dose scheduling of sunitinib on host immune response elements and vaccine combination therapy. Int J Cancer. 2012;130(8):1948–59.

    Article  CAS  PubMed  Google Scholar 

  152. Kwilas AR, Donahue RN, Tsang KY, Hodge JW. Immune consequences of tyrosine kinase inhibitors that synergize with cancer immunotherapy. Cancer Cell Microenviron. 2015;2(1), e677.

    PubMed  PubMed Central  Google Scholar 

  153. Amato RJ, Hawkins RE, Kaufman HL, Thompson JA, Tomczak P, Szczylik C, McDonald M, Eastty S, Shingler WH, de Belin J, Goonewardena M, Naylor S, Harrop R. Vaccination of metastatic renal cancer patients with MVA-5 T4: a randomized, double-blind, placebo-controlled phase III study. Clin Cancer Res. 2010;16(22):5539–47.

    Article  CAS  PubMed  Google Scholar 

  154. Franco M, Man S, Chen L, Emmenegger U, Shaked Y, Cheung AM, Brown AS, Hicklin DJ, Foster FS, Kerbel RS. Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia. Cancer Res. 2006;66(7):3639–48.

    Article  CAS  PubMed  Google Scholar 

  155. Moserle L, Jimenez-Valerio G, Casanovas O. Antiangiogenic therapies: going beyond their limits. Cancer Discov. 2014;4(1):31–41.

    Article  CAS  PubMed  Google Scholar 

  156. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21(2):137–48.

    Article  CAS  PubMed  Google Scholar 

  157. Jain RK, Au P, Tam J, Duda DG, Fukumura D. Engineered vascularized tissue. Nat Biotechnol. 2005;23(7):821–3.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Dr. Ronald Fecek for reviewing this manuscript.

No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Kellsye L. Fabian & Walter J. Storkus

  2. Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Walter J. Storkus

  3. University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA

    Walter J. Storkus

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  1. Kellsye L. Fabian
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Correspondence to Walter J. Storkus .

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  1. Institut Cochin INSERM, Université Paris Descartes, Paris, France

    Emmanuel Donnadieu

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Fabian, K.L., Storkus, W.J. (2016). Vascular Normalization, T Cell Trafficking and Anti-tumor Immunity. In: Donnadieu, E. (eds) Defects in T Cell Trafficking and Resistance to Cancer Immunotherapy. Resistance to Targeted Anti-Cancer Therapeutics, vol 9. Springer, Cham. https://doi.org/10.1007/978-3-319-42223-7_3

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