Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Anti-angiogenic agents — overcoming tumour endothelial cell anergy and improving immunotherapy outcomes

Abstract

Immune checkpoint inhibitors have revolutionized medical oncology, although currently only a subset of patients has a response to such treatment. A compelling body of evidence indicates that anti-angiogenic therapy has the capacity to ameliorate antitumour immunity owing to the inhibition of various immunosuppressive features of angiogenesis. Hence, combinations of anti-angiogenic agents and immunotherapy are currently being tested in >90 clinical trials and 5 such combinations have been approved by the FDA in the past few years. In this Perspective, we describe how the angiogenesis-induced endothelial immune cell barrier hampers antitumour immunity and the role of endothelial cell anergy as the vascular counterpart of immune checkpoints. We review the antitumour immunity-promoting effects of anti-angiogenic agents and provide an update on the current clinical successes achieved when these agents are combined with immune checkpoint inhibitors. Finally, we propose that anti-angiogenic agents are immunotherapies — and vice versa — and discuss future research priorities.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The endothelial immune cell barrier.
Fig. 2: Endothelial cell anergy.
Fig. 3: Molecular mechanisms of endothelial cell anergy.
Fig. 4: Endothelial cell anergy is a vascular immune checkpoint.

References

  1. 1.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Topalian, S. L., Taube, J. M., Anders, R. A. & Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275–287 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    O’Donnell, J. S., Teng, M. W. L. & Smyth, M. J. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol. 16, 151–167 (2019).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  14. 14.

    Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Vanneman, M. & Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12, 237–251 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Griffioen, A. W. & Molema, G. Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol. Rev. 52, 237–268 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Rahma, O. E. & Hodi, F. S. The intersection between tumor angiogenesis and immune suppression. Clin. Cancer Res. 25, 5449–5457 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Motz, G. T. & Coukos, G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat. Rev. Immunol. 11, 702–711 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Hicklin, D. J. & Ellis, L. M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J. Clin. Oncol. 23, 1011–1027 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Gabrilovich, D. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2, 1096–1103 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Wada, J. et al. The contribution of vascular endothelial growth factor to the induction of regulatory T- cells in malignant effusions. Anticancer. Res. 29, 881–888 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Terme, M. et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 73, 539–549 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Huang, Y. et al. Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood 110, 624–631 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Ohm, J. E. et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 101, 4878–4886 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Gavalas, N. G. et al. VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2. Br. J. Cancer 107, 1869–1875 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Khan, K. A. & Kerbel, R. S. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat. Rev. Clin. Oncol. 15, 310–324 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Griffioen, A., Damen, C., Blijham, G. & Groenewegen, G. Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood 88, 667–673 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Dirkx, A. E. M. et al. Tumor angiogenesis modulates leukocyte-vessel wall interactions in Vivo by reducing endothelial adhesion molecule expression. Cancer Res. 63, 2322–2329 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Griffioen, A. W., Damen, C. A., Martinotti, S., Blijham, G. H. & Groenewegen, G. Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res. 56, 1111–1117 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Gajewski, T. F. et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr. Opin. Immunol. 25, 268–276 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  33. 33.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Gajewski, T. F. The next hurdle in cancer immunotherapy: overcoming the non–T-cell–inflamed tumor microenvironment. Semin. Oncol. 42, 663–671 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Galon, J. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Hegde, P. S., Karanikas, V. & Evers, S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin. Cancer Res. 22, 1865–1874 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Carmeliet, P. VEGF as a key mediator of angiogenesis in cancer. Oncology 69, 4–10 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Chouaib, S., Noman, M. Z., Kosmatopoulos, K. & Curran, M. A. Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer. Oncogene 36, 439–445 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G. & Jain, R. K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 325–340 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Huang, Y. et al. Improving immune–vascular crosstalk for cancer immunotherapy. Nat. Rev. Immunol. 18, 195–203 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Ramjiawan, R. R., Griffioen, A. W. & Duda, D. G. Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? Angiogenesis 20, 185–204 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Motzer, R. J. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1103–1115 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Makker, V. et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 20, 711–718 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Chen, D. S. & Hurwitz, H. Combinations of bevacizumab with cancer immunotherapy. Cancer J. 24, 193–204 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Pober, J. S. & Sessa, W. C. Evolving functions of endothelial cells in inflammation. Nat. Rev. Immunol. 7, 803–815 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Vestweber, D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol. 15, 692–704 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    von Andrian, U. H. & Mackay, C. R. T-cell function and migration — two sides of the same coin. N. Engl. J. Med. 343, 1020–1034 (2000).

    Article  Google Scholar 

  55. 55.

    Bevilacqua, M. P. Endothelial-leukcoyte adhesion molecules. Annu. Rev. Immuonol. 11, 767–804 (1993).

    CAS  Article  Google Scholar 

  56. 56.

    Springer, T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm. Cell 76, 301–314 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Klein, D. The tumor vascular endothelium as decision maker in cancer therapy. Front. Oncol. 8, 367 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Kuzu, I. et al. Heterogeneity of vascular endothelial cells with relevance to diagnosis of vascular tumours. J. Clin. Pathol. 45, 143–148 (1992).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Berger, R. et al. Expression of platelet-endothelial cell adhesion molecule-1 (PECAM-1) during melanoma-induced angiogenesis in vivo. J. Cutan. Pathol. 20, 399–406 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Dewhirst, M. W. & Dewhirst, M. W. Diminished leukocyte-endothelium interaction in tumor microvessels. Cancer Res. 52, 4265–4268 (1992).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Shibata, Y. et al. Suppressive effect of basic fibroblast growth factor on transendothelial emigration of CD4+ T-lymphocyte. Cancer Res. 54, 4729–4733 (1994).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Piali, L., Fichtel, A., Terpe, H. J., Imhof, B. A. & Gisler, R. H. Endothelial vascular cell adhesion molecule 1 expression is suppressed by melanoma and carcinoma. J. Exp. Med. 181, 811–816 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    Fukumura, D. et al. Tumor necrosis factor α-induced leukocyte adhesion in normal and tumor vessels: effect of tumor type, transplantation site, and host strain. Cancer Res. 55, 4824–4829 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Schmidt, J. et al. Reduced basal and stimulated leukocyte adherence in tumor endothelium of experimental pancreatic cancer. Int. J. Gastrointest. Cancer 26, 173–180 (1999).

    CAS  Article  Google Scholar 

  65. 65.

    Tromp, S. C. et al. Tumor angiogenesis factors reduce leukocyte adhesion in vivo. Int. Immunol. 12, 671–676 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Bouma-ter Steege, J. C. et al. Angiogenic profile of breast carcinoma determines leukocyte infiltration. Clin. Cancer Res. 10, 7171–7178 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Flati, V. et al. Endothelial cell anergy is mediated by bFGF through the sustained activation of p38-MAPK and NF-κB inhibition. Int. J. Immunopathol. Pharmacol. 19, 761–773 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Hellebrekers, D. M. E. I. et al. Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications. Cancer Res. 66, 10770–10777 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Kubes, P., Suzuki, M. & Granger, D. N. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc. Natl Acad. Sci. USA 88, 4651–4655 (1991).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    De Caterina, R. et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J. Clin. Invest. 96, 60–68 (1995).

    PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    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 anergy. J. Immunol. 178, 1505–1511 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Buckanovich, R. J. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat. Med. 14, 28–36 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Melder, R. J. et al. During angiogenesis, vascular endothelial growth factor regulate natural killer cell adhesion to tumor endothelium. Nat. Med. 2, 992–997 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Kevil, C. G. et al. Intercellular adhesion molecule-1 (ICAM-1) regulates endothelial cell motility through a nitric oxide-dependent pathway. J. Biol. Chem. 279, 19230–19238 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Agata, Y. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765–772 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Baitsch, L. et al. Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J. Clin. Invest. 121, 2350–2360 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Nussbaum, C. et al. Neutrophil and endothelial adhesive function during human fetal ontogeny. J. Leukoc. Biol. 93, 175–184 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Larson, B. J., Longaker, M. T. & Lorenz, H. P. Scarless fetal wound healing: a basic science review. Plast. Reconstr. Surg. 126, 1172–1180 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Lo, D. D., Zimmermann, A. S., Nauta, A., Longaker, M. T. & Lorenz, H. P. Scarless fetal skin wound healing update. Birth Defects Res. C. Embryo Today Rev. 96, 237–247 (2012).

    CAS  Article  Google Scholar 

  83. 83.

    Reinke, J. M. & Sorg, H. Wound repair and regeneration. Eur. Surg. Res. 49, 35–43 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    Demir, R., Seval, Y. & Huppertz, B. Vasculogenesis and angiogenesis in the early human placenta. Acta Histochem. 109, 257–265 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. 85.

    Shechter, R., London, A. & Schwartz, M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat. Rev. Immunol. 13, 206–218 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Hua, Y. & Bergers, G. Tumors vs. chronic wounds: an immune cell’s perspective. Front. Immunol. 10, 2178 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Landén, N. X., Li, D. & Ståhle, M. Transition from inflammation to proliferation: a critical step during wound healing. Cell. Mol. Life Sci. 73, 3861–3885 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. 88.

    De Palma, M., Biziato, D. & Petrova, T. V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17, 457–474 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  89. 89.

    Missiaen, R., Mazzone, M. & Bergers, G. The reciprocal function and regulation of tumor vessels and immune cells offers new therapeutic opportunities in cancer. Semin. Cancer Biol. 52, 107–116 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Zou, W. & Chen, L. Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol. 8, 467–477 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Flier, J. S., Underhill, L. H. & Dvorak, H. F. Tumors: wounds that do not heal. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  Google Scholar 

  94. 94.

    Topalian, S. L. et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Gettinger, S. N. et al. Overall survival and long-term safety of nivolumab (Anti–programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non–small-cell lung cancer. J. Clin. Oncol. 33, 2004–2012 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Topalian, S. L. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Griffioen, A. W. et al. Angiogenesis inhibitors overcome tumor induced endothelial cell anergy. Int. J. Cancer 80, 315–319 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  98. 98.

    Tabruyn, S. P. et al. The angiostatic 16K human prolactin overcomes endothelial cell anergy and promotes leukocyte infiltration via nuclear factor-κB activation. Mol. Endocrinol. 21, 1422–1429 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. 99.

    Zhang, H. & Issekutz, A. C. Down-modulation of monocyte transendothelial migration and endothelial adhesion molecule expression by fibroblast growth factor. Am. J. Pathol. 160, 2219–2230 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Dirkx, A. E. M. et al. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. FASEB J. 20, 621–630 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    Dings, R. P. M. et al. Enhancement of T-cell-mediated antitumor response: angiostatic adjuvant to immunotherapy against cancer. Clin. Cancer Res. 17, 3134–3145 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Thijssen, V. L., Heusschen, R., Caers, J. & Griffioen, A. W. Galectin expression in cancer diagnosis and prognosis: a systematic review. Biochim. Biophys. Acta Rev. Cancer 1855, 235–247 (2015).

    CAS  Article  Google Scholar 

  103. 103.

    Thijssen, V. L. J. L. et al. Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc. Natl Acad. Sci. USA 103, 15975–15980 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Rabinovich, G. A. & Toscano, M. A. Turning ‘sweet’ on immunity: galectin–glycan interactions in immune tolerance and inflammation. Nat. Rev. Immunol. 9, 338–352 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. 105.

    Perillo, N. L., Pace, K. E., Seilhamer, J. J. & Baum, L. G. Apoptosis of T cells mediated by galectin-1. Nature 378, 736–739 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  106. 106.

    Chung, C. D., Patel, V. P., Moran, M., Lewis, L. A. & Miceli, M. C. Galectin-1 induces partial TCR ζ-chain phosphorylation and antagonizes processive TCR signal transduction. J. Immunol. 165, 3722–3729 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. 107.

    Blaser, C. et al. β-Galactoside-binding protein secreted by activated T cells inhibits antigen-induced proliferation of T cells. Eur. J. Immunol. 28, 2311–2319 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Matarrese, P. et al. Galectin-1 sensitizes resting human T lymphocytes to Fas (CD95)-mediated cell death via mitochondrial hyperpolarization, budding, and fission. J. Biol. Chem. 280, 6969–6985 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Clausse, N., Van Den Brûle, F., Waltregny, D., Garnier, F. & Castronovo, V. Galectin-1 expression in prostate tumor-associated capillary endothelial cells is increased by prostate carcinoma cells and modulates heterotypic cell-cell adhesion. Angiogenesis 3, 317–325 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. 110.

    He, J. & Baum, L. G. Endothelial cell expression of galectin-1 induced by prostate cancer cells inhibits T-cell transendothelial migration. Lab. Invest. 86, 578–590 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Norling, L. V., Sampaio, A. L. F., Cooper, D. & Perretti, M. Inhibitory control of endothelial galectin-1 on in vitro and in vivo lymphocyte trafficking. FASEB J. 22, 682–690 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  112. 112.

    La, M. et al. A novel biological activity for galectin-1. Am. J. Pathol. 163, 1505–1515 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Rubinstein, N. et al. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection. Cancer Cell 5, 241–251 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Dalotto-Moreno, T. et al. Targeting galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease. Cancer Res. 73, 1107–1117 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  115. 115.

    Nambiar, D. K. et al. Galectin-1–driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance. J. Clin. Invest. 129, 5553–5567 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Huang, X. et al. Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion. J. Exp. Med. 207, 505–520 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Rodig, N. et al. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur. J. Immunol. 33, 3117–3126 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    Mazanet, M. M. & Hughes, C. C. W. B7-H1 Is expressed by human endothelial cells and suppresses T cell cytokine synthesis. J. Immunol. 169, 3581–3588 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  120. 120.

    Grabie, N. et al. Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell–mediated injury in the heart. Circulation 116, 2062–2071 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. 121.

    Chen, W.-J. et al. Human umbilical vein endothelial cells promote the inhibitory activation of CD4+ CD25+ Foxp3+ regulatory T cells via PD-L1. Atherosclerosis 244, 108–112 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    Kamada, T. et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc. Natl Acad. Sci. USA 116, 9999–10008 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Kumagai, S. et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat. Immunol. 21, 1346–1358 (2020).

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Liu, S. et al. anlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vascular endothelial cells. Cell Death Dis. 11, 309 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. 125.

    Allen, E. et al. Combined antiangiogenic and anti–PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl Med. 9, eaak9679 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. 126.

    Shigeta, K. et al. Dual programmed death receptor-1 and vascular endothelial growth factor receptor-2 blockade promotes vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma. Hepatology 71, 1247–1261 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  127. 127.

    Schmittnaegel, M. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl Med. 9, eaak9670 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  128. 128.

    Riesenberg, R. 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. 13, 6993–7002 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. 129.

    Blaschitz, A. et al. Vascular endothelial expression of indoleamine 2,3-dioxygenase 1 forms a positive gradient towards the feto-maternal interface. PLoS ONE 6, e21774 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Shetty, S. et al. Common lymphatic endothelial and vascular endothelial receptor-1 mediates the transmigration of regulatory T cells across human hepatic sinusoidal endothelium. J. Immunol. 186, 4147–4155 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  131. 131.

    Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Ebos, J. M. L. & Kerbel, R. S. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat. Rev. Clin. Oncol. 8, 210–221 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Bajou, K. et al. PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin. Nat. Med. 20, 741–747 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  134. 134.

    Griffioen, A. W. et al. Anginex, a designed peptide that inhibits angiogenesis. Biochem. J. 354, 233 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Kim, M. S. et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat. Med. 7, 437–443 (2001).

    PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Hellebrekers, D. M. E. I. et al. Angiostatic activity of DNA methyltransferase inhibitors. Mol. Cancer Ther. 5, 467–475 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  137. 137.

    Huang, Y. et al. Dual-mechanism based CTLs infiltration enhancement initiated by Nano-sapper potentiates immunotherapy against immune-excluded tumors. Nat. Commun. 11, 622 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Weishaupt, C. et al. Activation of human vascular endothelium in melanoma metastases induces ICAM-1 and E-selectin expression and results in increased infiltration with effector lymphocytes. Exp. Dermatol. 28, 1258–1269 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. 139.

    Calcinotto, A. et al. Targeting TNF-α to neoangiogenic vessels enhances lymphocyte infiltration in tumors and increases the therapeutic potential of immunotherapy. J. Immunol. 188, 2687–2694 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  140. 140.

    Fisher, D. T. et al. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J. Clin. Invest. 121, 3846–3859 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Gabrilovich, D. I., Ishida, T., Nadaf, S., Ohm, J. E. & Carbone, D. P. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin. Cancer Res. 5, 2963–2970 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Ishida, T., Oyama, T., Carbone, D. P. & Gabrilovich, D. I. Defective function of langerhans cells in tumor-bearing animals is the result of defective maturation from hemopoietic progenitors. J. Immunol. 161, 4842–4851 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Manzoni, M. et al. Immunological effects of bevacizumab-based treatment in metastatic colorectal cancer. Oncology 79, 187–196 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  144. 144.

    Martino, E. et al. Immune-modulating effects of bevacizumab in metastatic non-small-cell lung cancer patients. Cell Death Discov. 2, 16025 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Ozao-Choy, J. 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. 69, 2514–2522 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Finke, J. H. et al. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin. Cancer Res. 14, 6674–6682 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  147. 147.

    Adotevi, O. et al. A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J. Immunother. 33, 991–998 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  148. 148.

    Ko, J. S. et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin. Cancer Res. 15, 2148–2157 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  149. 149.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  150. 150.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  151. 151.

    Weiss, A. et al. Angiostatic treatment prior to chemo- or photodynamic therapy improves anti-tumor efficacy. Sci. Rep. 5, 8990 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Shrimali, R. K. et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 70, 6171–6180 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561–17566 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  155. 155.

    Mazzieri, R. et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19, 512–526 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  156. 156.

    Di Tacchio, M. et al. Tumor vessel normalization, immunostimulatory reprogramming, and improved survival in glioblastoma with combined inhibition of PD-1, angiopoietin-2, and VEGF. Cancer Immunol. Res. 7, 1910–1927 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  157. 157.

    Johansson-Percival, A. et al. Intratumoral LIGHT restores pericyte contractile properties and vessel integrity. Cell Rep. 13, 2687–2698 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  158. 158.

    He, B. et al. Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules. J. Pathol. 245, 209–221 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159.

    Johansson-Percival, A. et al. De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors. Nat. Immunol. 18, 1207–1217 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  160. 160.

    Otterdal, K. et al. Platelet-derived LIGHT induces inflammatory responses in endothelial cells and monocytes. Blood 108, 928–935 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  161. 161.

    Girard, J.-P. & Springer, T. A. High endothelial venules (HEVs): specialized endothelium for lymphocyte migration. Immunol. Today 16, 449–457 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  162. 162.

    Milutinovic, S., Abe, J., Godkin, A., Stein, J. V. & Gallimore, A. The dual role of high endothelial venules in cancer progression versus immunity. Trends Cancer 7, 214–225 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  163. 163.

    Sawa, Y. et al. Immunohistochemical study on leukocyte adhesion molecules expressed on lymphatic endothelium. Microvasc. Res. 57, 292–297 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  164. 164.

    Guislain, A. et al. Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma. Cancer Immunol. Immunother. 64, 1241–1250 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  165. 165.

    Ragusa, S. et al. Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice. J. Clin. Invest. 130, 1199–1216 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    Li, H. et al. CAIX-specific CAR-T cells and sunitinib show synergistic effects against metastatic renal cancer models. J. Immunother. 43, 16–28 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  167. 167.

    Bocca, P. et al. Bevacizumab-mediated tumor vasculature remodelling improves tumor infiltration and antitumor efficacy of GD2-CAR T cells in a human neuroblastoma preclinical model. Oncoimmunology 7, e1378843 (2018).

    Article  Google Scholar 

  168. 168.

    Manning, E. A. et al. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin. Cancer Res. 13, 3951–3959 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  169. 169.

    Yasuda, S. et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin. Exp. Immunol. 172, 500–506 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  170. 170.

    Leenders, W. P. J., Küsters, B. & de Waal, R. M. W. Vessel co-option: how tumors obtain blood supply in the absence of sprouting angiogenesis. Endothelium 9, 83–87 (2002).

    PubMed  Article  PubMed Central  Google Scholar 

  171. 171.

    Maniotis, A. J. et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am. J. Pathol. 155, 739–752 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. 172.

    Kuczynski, E. A., Vermeulen, P. B., Pezzella, F., Kerbel, R. S. & Reynolds, A. R. Vessel co-option in cancer. Nat. Rev. Clin. Oncol. 16, 469–493 (2019).

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Bridgeman, V. L. et al. Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J. Pathol. 241, 362–374 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  174. 174.

    Hu, J. et al. Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer. Oncogene 24, 1212–1219 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  175. 175.

    Van den Eynden, G. G. et al. The histological growth pattern of colorectal cancer liver metastases has prognostic value. Clin. Exp. Metastasis 29, 541–549 (2012).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  176. 176.

    Van Dam, P. J. et al. Histopathological growth patterns as a candidate biomarker for immunomodulatory therapy. Semin. Cancer Biol. 52, 86–93 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  177. 177.

    Hendrix, M. J. C., Seftor, E. A., Hess, A. R. & Seftor, R. E. B. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat. Rev. Cancer 3, 411–421 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  178. 178.

    Paulis, Y. W. J., Soetekouw, P. M. M. B., Verheul, H. M. W., Tjan-Heijnen, V. C. G. & Griffioen, A. W. Signalling pathways in vasculogenic mimicry. Biochim. Biophys. Acta Rev. Cancer 1806, 18–28 (2010).

    CAS  Article  Google Scholar 

  179. 179.

    van der Schaft, D. W. J. et al. Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia. Cancer Res. 65, 11520–11528 (2005).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  180. 180.

    van der Schaft, D. W. J. et al. Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells. J. Natl Cancer Inst. 96, 1473–1477 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  181. 181.

    Vartanian, A. et al. Inhibitor of vasculogenic mimicry restores sensitivity of resistant melanoma cells to DNA-damaging agents. Melanoma Res. 27, 8–16 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  182. 182.

    van Beijnum, J. R., Nowak-Sliwinska, P., Huijbers, E. J. M., Thijssen, V. L. & Griffioen, A. W. The great escape; the hallmarks of resistance to antiangiogenic therapy. Pharmacol. Rev. 67, 441–461 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  183. 183.

    Makker, V. et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J. Clin. Oncol. 38, 2981–2992 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Motzer, R. J. et al. Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial. Nat. Med. 26, 1733–1741 (2020).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  185. 185.

    McDermott, D. F. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24, 749–757 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  187. 187.

    Braun, D. A. et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat. Med. 26, 909–918 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  188. 188.

    Lan, C. et al. Camrelizumab plus apatinib in patients with advanced cervical cancer (CLAP): a multicenter, open-label, single-arm, phase II trial. J. Clin. Oncol. 38, 4095–4106 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  189. 189.

    Jaini, R., Rayman, P., Cohen, P. A., Finke, J. H. & Tuohy, V. K. Combination of sunitinib with anti-tumor vaccination inhibits T cell priming and requires careful scheduling to achieve productive immunotherapy. Int. J. Cancer 134, 1695–1705 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  190. 190.

    Liu, X.-D. et al. Resistance to antiangiogenic therapy is associated with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma. Cancer Immunol. Res. 3, 1017–1029 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    Taube, J. M. et al. Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl Med. 4, 127ra37 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  192. 192.

    Ciciola, P., Cascetta, P., Bianco, C., Formisano, L. & Bianco, R. Combining immune checkpoint inhibitors with anti-angiogenic agents. J. Clin. Med. 9, 675 (2020).

    CAS  PubMed Central  Article  Google Scholar 

  193. 193.

    Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. 194.

    Wentink, M. Q. et al. Vaccination approach to anti-angiogenic treatment of cancer. Biochim. Biophys. Acta Rev. Cancer 1855, 155–171 (2015).

    CAS  Article  Google Scholar 

  195. 195.

    Jackson, H. J., Rafiq, S. & Brentjens, R. J. Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 13, 370–383 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. 196.

    Kakarla, S. & Gottschalk, S. CAR T cells for solid tumors. Cancer J. 20, 151–155 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    Akbari, P., Huijbers, E. J. M., Themeli, M., Griffioen, A. W. & van Beijnum, J. R. The tumor vasculature an attractive CAR T cell target in solid tumors. Angiogenesis 22, 473–475 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  198. 198.

    Niethammer, A. G. et al. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat. Med. 8, 1369–1375 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  199. 199.

    Facciponte, J. G. et al. Tumor endothelial marker 1–specific DNA vaccination targets tumor vasculature. J. Clin. Invest. 124, 1497–1511 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. 200.

    Wentink, M. Q. et al. Targeted vaccination against the bevacizumab binding site on VEGF using 3D-structured peptides elicits efficient antitumor activity. Proc. Natl Acad. Sci. USA 113, 12532–12537 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  201. 201.

    Huijbers, E. J. M. et al. Vaccination against the extra domain-B of fibronectin as a novel tumor therapy. FASEB J. 24, 4535–4544 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  202. 202.

    Zhuang, X. et al. Robo4 vaccines induce antibodies that retard tumor growth. Angiogenesis 18, 83–95 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  203. 203.

    Huijbers, E. J. M. et al. Targeting tumor vascular CD99 inhibits tumor growth. Front. Immunol. 10, 651 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  204. 204.

    Scalia, R., Booth, G. & Lefer, D. J. Vascular endothelial growth factor attenuates leukocyte–endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide. FASEB J. 13, 1039–1046 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  205. 205.

    Minshall, R. D., Sessa, W. C., Stan, R. V., Anderson, R. G. W. & Malik, A. B. Caveolin regulation of endothelial function. Am. J. Physiol. Cell. Mol. Physiol. 285, L1179–L1183 (2003).

    CAS  Article  Google Scholar 

  206. 206.

    Weiss, A. et al. Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer. Angiogenesis 18, 233–244 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 207.

    Nowak-Sliwinska, P. et al. Optimization of drug combinations using feedback system control. Nat. Protoc. 11, 302–315 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  208. 208.

    Ho, D. Artificial intelligence in cancer therapy. Science 367, 982–983 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  209. 209.

    Sicklick, J. K. et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat. Med. 25, 744–750 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  210. 210.

    Mougel, A., Terme, M. & Tanchot, C. Therapeutic cancer vaccine and combinations with antiangiogenic therapies and immune checkpoint blockade. Front. Immunol. 10, 467 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  211. 211.

    Argentiero, A. et al. Anti-angiogenesis and immunotherapy: novel paradigms to envision tailored approaches in renal cell-carcinoma. J. Clin. Med. 9, 1594 (2020).

    CAS  PubMed Central  Article  Google Scholar 

  212. 212.

    Galluzzi, L., Humeau, J., Buqué, A., Zitvogel, L. & Kroemer, G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat. Rev. Clin. Oncol. 17, 725–741 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  213. 213.

    Formenti, S. C. et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat. Med. 24, 1845–1851 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The work of P.N-S. is funded by the Swiss National Science Foundation (grant 310030_197878). The work of A.W.G. is supported by the KWF Cancer Society (grant 2018–11651).

Author information

Affiliations

Authors

Contributions

Z.R.H. and A.W.G. researched data for this article. All authors contributed to all other aspects of preparation of this manuscript.

Corresponding authors

Correspondence to Patrycja Nowak-Sliwinska or Arjan W. Griffioen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Clinical Oncology thanks M. de Palma, who co-reviewed with A. Martinez-Usatorre, R. Kerbel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

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

Related links

ClinicalTrials.gov database: https://clinicaltrials.gov

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Huinen, Z.R., Huijbers, E.J.M., van Beijnum, J.R. et al. Anti-angiogenic agents — overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat Rev Clin Oncol 18, 527–540 (2021). https://doi.org/10.1038/s41571-021-00496-y

Download citation

Further reading

Search

Quick links