Burnet, F. M. The concept of immunological surveillance. Prog. Exp. Tumor Res. 13, 1–27 (1970).
Burnet, M. Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br. Med. J. 1, 841–847 (1957).
Shankaran, V. et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).
Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
Khalil, D. N., Smith, E. L., Brentjens, R. J. & Wolchok, J. D. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat. Rev. Clin. Oncol. 13, 273–290 (2016).
Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl Med. 3, 95ra73 (2011).
Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).
Eshhar, Z. & Gross, G. Chimeric T cell receptor which incorporates the anti-tumour specificity of a monoclonal antibody with the cytolytic activity of T cells: a model system for immunotherapeutical approach. Br. J. Cancer. Suppl. 10, 27–29 (1990).
Mayordomo, J. I. et al. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity. Nat. Med. 1, 1297–1302 (1995).
Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).
Schlom, J. Therapeutic cancer vaccines: current status and moving forward. J. Natl Cancer Inst. 104, 599–613 (2012).
Madan, R. A., Gulley, J. L., Fojo, T. & Dahut, W. L. Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression. Oncologist 15, 969–975 (2010).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016).
Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).
Nghiem, P. T. et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N. Engl. J. Med. 374, 2542–2552 (2016).
Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).
Spitzer, M. H. et al. Systemic immunity is required for effective cancer immunotherapy. Cell 168, 487–502 (2017).
Ganss, R., Arnold, B. & Hammerling, G. J. Mini-review: overcoming tumor-intrinsic resistance to immune effector function. Eur. J. Immunol. 34, 2635–2641 (2004).
Motz, G. T. & Coukos, G. Deciphering and reversing tumor immune suppression. Immunity 39, 61–73 (2013).
Huang, Y., Goel, S., Duda, D. G., Fukumura, D. & Jain, R. K. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 73, 2943–2948 (2013).
Lanitis, E., Irving, M. & Coukos, G. Targeting the tumor vasculature to enhance T cell activity. Curr. Opin. Immunol. 33, 55–63 (2015).
Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).
Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).
Kourembanas, S., Hannan, R. L. & Faller, D. V. Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. J. Clin. Invest. 86, 670–674 (1990).
Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).
Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014).
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).
Wu, N. Z., Klitzman, B., Dodge, R. & Dewhirst, M. W. Diminished leukocyte-endothelium interaction in tumor microvessels. Cancer Res. 52, 4265–4268 (1992).
Muller, W. A. Mechanisms of leukocyte transendothelial migration. Annu. Rev. Pathol. 6, 323–344 (2011).
Griffioen, A. W. et al. Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res. 56, 1111–1117 (1996).
Nagarsheth, N., Wicha, M. S. & Zou, W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat. Rev. Immunol. 17, 559–572 (2017).
Tang, H. et al. Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell 29, 285–296 (2016).
Jiang, W., Chan, C. K., Weissman, I. L., Kim, B. Y. S. & Hahn, S. M. Immune priming of the tumor microenvironment by radiation. Trends Cancer 2, 638–645 (2016).
Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 22, 851–860 (2016).
Taylor, C. T. & Colgan, S. P. Regulation of immunity and inflammation by hypoxia in immunological niches. Nat. Rev. Immunol. 17, 774–785 (2017).
Corzo, C. A. et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207, 2439–2453 (2010).
Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).
Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).
Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).
Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475, 226–230 (2011).
Doedens, A. L. et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res. 70, 7465–7475 (2010).
Klages, K. et al. Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res. 70, 7788–7799 (2010).
Barsoum, I. B., Smallwood, C. A., Siemens, D. R. & Graham, C. H. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 74, 665–674 (2014).
Zhou, Y. et al. PD-1 and PD-L1 expression in 132 recurrent nasopharyngeal carcinoma: the correlation with anemia and outcomes. Oncotarget 8, 51210–51223 (2017).
Ruf, M., Moch, H. & Schraml, P. PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma. Int. J. Cancer 139, 396–403 (2016).
Koh, J. et al. EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)-1alpha and STAT3. Oncoimmunology 5, e1108514 (2016).
Koh, H. S. et al. The HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia. Nat. Commun. 6, 6340 (2015).
Noman, M. Z. et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211, 781–790 (2014).
Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015).
Sitkovsky, M. V., Kjaergaard, J., Lukashev, D. & Ohta, A. Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin. Cancer Res. 14, 5947–5952 (2008).
Fischer, K. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819 (2007).
Gottfried, E. et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107, 2013–2021 (2006).
Huber, V. et al. Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin. Cancer Biol. 43, 74–89 (2017).
Mendler, A. N. et al. Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int. J. Cancer 131, 633–640 (2012).
Park, J. S. et al. Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell 30, 953–967 (2016).
Jiang, W., Huang, Y., An, Y. & Kim, B. Y. S. Remodeling tumor vasculature to enhance delivery of intermediate-sized nanoparticles. ACS Nano 9, 8689–8696 (2015).
Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008).
Liu, Y. et al. Regulation of leukocyte transmigration: cell surface interactions and signaling events. J. Immunol. 172, 7–13 (2004).
Huang, Y., Stylianopoulos, T., Duda, D. G., Fukumura, D. & Jain, R. K. Benefits of vascular normalization are dose and time dependent. Cancer Res. 73, 7144–7146 (2013).
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).
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).
Rahbari, N. N. et al. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci. Transl Med. 8, 360ra135 (2016).
Jung, K. et al. Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J. Clin. Invest. 127, 3039–3051 (2017).
Hatfield, S. M. et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Transl Med. 7, 277ra30 (2015).
Mazzieri, R. 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).
Hashizume, H. et al. Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res. 70, 2213–2223 (2010).
Peterson, T. E. et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc. Natl Acad. Sci. USA 113, 4470–4475 (2016).
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).
Kloepper, J. et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc. Natl Acad. Sci. USA 113, 4476–4481 (2016).
Allen, E. et al. Combined antiangiogenic and anti–PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl Med. 9, eaak9679 (2017).
Benci, J. L. et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167, 1540–1554 (2016).
Carretero, R. et al. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells. Nat. Immunol. 16, 609–617 (2015).
Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017).
Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010).
Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).
Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).
June, C. H., Warshauer, J. T. & Bluestone, J. A. Is autoimmunity the Achilles' heel of cancer immunotherapy? Nat. Med. 23, 540–547 (2017).
Kamphorst, A. O. et al. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355, 1423–1427 (2017).
Huang, A. C. et al. T-Cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545, 60–65 (2017).
Ruegg, C. et al. Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat. Med. 4, 408–414 (1998).
Beatty, G. L. & Paterson, Y. IFN-γ-dependent inhibition of tumor angiogenesis by tumor-infiltrating CD4+ T cells requires tumor responsiveness to IFN-γ. J. Immunol. 166, 2276–2282 (2001).
Hayakawa, Y. et al. IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide. Blood 100, 1728–1733 (2002).
Ohm, J. E. et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 101, 4878–4886 (2003).
Gabrilovich, D. I. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2, 1096–1103 (1996).
Huang, Y. et al. Resuscitating cancer immunosurveillance: selective stimulation of DLL1-Notch signaling in T cells rescues T-cell function and inhibits tumor growth. Cancer Res. 71, 6122–6131 (2011).
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).
Romagnani, P., Lasagni, L., Annunziato, F., Serio, M. & Romagnani, S. CXC chemokines: the regulatory link between inflammation and angiogenesis. Trends Immunol. 25, 201–209 (2004).
Arenberg, D. A. et al. Interferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases. J. Exp. Med. 184, 981–992 (1996).
Fathallah-Shaykh, H. M., Zhao, L. J., Kafrouni, A. I., Smith, G. M. & Forman, J. Gene transfer of IFN-gamma into established brain tumors represses growth by antiangiogenesis. J. Immunol. 164, 217–222 (2000).
Kammertoens, T. et al. Tumour ischaemia by interferon-gamma resembles physiological blood vessel regression. Nature 545, 98–102 (2017).
De Palma, M., Biziato, D. & Petrova, T. V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17, 457–474 (2017).
Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).
Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).
Murdoch, C., Muthana, M., Coffelt, S. B. & Lewis, C. E. The role of myeloid cells in the promotion of tumour angiogenesis. Nat. Rev. Cancer 8, 618–631 (2008).
Yang, L. et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6, 409–421 (2004).
Lewis, C. E., Harney, A. S. & Pollard, J. W. The multifaceted role of perivascular macrophages in tumors. Cancer Cell 30, 18–25 (2016).
Kessenbrock, K., Plaks, V. & Werb, Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52–67 (2010).
Huang, S. et al. Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J. Natl Cancer Inst. 94, 1134–1142 (2002).
Huang, Y., Snuderl, M. & Jain, R. K. Polarization of tumor-associated macrophages: a novel strategy for vascular normalization and antitumor immunity. Cancer Cell 19, 1–2 (2011).
Rolny, C. et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19, 31–44 (2011).
Nishino, M., Ramaiya, N. H., Hatabu, H. & Hodi, F. S. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat. Rev. Clin. Oncol. 14, 655–668 (2017).
Rigamonti, N. et al. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 8, 696–706 (2014).
Goede, V. et al. Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br. J. Can. 103, 1407–1414 (2010).
De Palma, M. & Naldini, L. Angiopoietin-2 TIEs up macrophages in tumour angiogenesis. Clin. Cancer Res. 17, 5226–5232 (2011).
Wu, W. et al. Angiopoietin-2 as a biomarker and target for immune checkpoint therapy. Can. Immunol. Res. 5, 17–28 (2017).
Piesche, M. et al. Angiogenic cytokines are antibody targets during graft-versus-leukemia reactions. Clin. Cancer Res. 21, 1010–1018 (2015).
Schoenfeld, J. et al. Active immunotherapy induces antibody responses that target tumor angiogenesis. Cancer Res. 70, 10150–10160 (2010).
Zahra, M. A. et al. Dynamic contrast-enhanced MRI as a predictor of tumour response to radiotherapy. Lancet Oncol. 8, 63–74 (2007).
Padhani, A. R. & Miles, K. A. Multiparametric imaging of tumor response to therapy. Radiology 256, 348–364 (2010).
Martinet, L. et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 71, 5678–5687 (2011).
Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).
Vanneman, M. & Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12, 237–251 (2012).
Gotwals, P. et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat. Rev. Cancer 17, 286–301 (2017).
Kang, J., Demaria, S. & Formenti, S. Current clinical trials testing the combination of immunotherapy with radiotherapy. J. Immunother. Cancer 4, 51–70 (2016).
Bernstein, M. B., Krishnan, S., Hodge, J. W. & Chang, J. Y. Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? Nat. Rev. Clin. Oncol. 13, 516–524 (2016).
Demaria, S., Coleman, C. N. & Formenti, S. C. Radiotherapy: changing the game in immunotherapy. Trends Cancer 2, 286–294 (2016).
Klug, F. et al. Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24, 589–602 (2013).
De Palma, M., Coukos, G. & Hanahan, D. A new twist on radiation oncology: low-dose irradiation elicits immunostimulatory macrophages that unlock barriers to tumor immunotherapy. Cancer Cell 24, 559–561 (2013).
Filatenkov, A. et al. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin. Cancer Res. 21, 3727–3739 (2015).
Stylianopoulosa, T. & Jain, R. K. Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc. Natl Acad. Sci. USA 110, 18632–18637 (2013).
Jain, R. K., Tong, R. T. & Munn, L. L. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: Insights from a mathematical model. Cancer Res. 67, 2729–2735 (2007).
Lund, A. W. Rethinking lymphatic vessels and antitumor immunity. Trends Cancer 2, 548–551 (2016).
Rotin, D., Robinson, B. & Tannock, I. F. Influence of hypoxia and an acidic environment on the metabolism and viability of cultured cells: potential implications for cell death in tumors. Cancer Res. 46, 2821–2826 (1986).
Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016).
Maj, T. et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumour. Nat. Immunol. 18, 1332–1341 (2017).
Tang, H., Qiao, J. & Fu, Y. X. Immunotherapy and tumor microenvironment. Cancer Lett. 370, 85–90 (2016).
Doedens, A. L. et al. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. Immunol. 4, 1173–1182 (2013).