VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors
Thibault Voron, Orianne Colussi, Elie Marcheteau, Simon Pernot, Mevyn Nizard, Anne-Laure Pointet, Sabrina Latreche, Sonia Bergaya, Nadine Benhamouda, Corinne Tanchot, Christian Stockmann, Pierre Combe, Anne Berger, Franck Zinzindohoue, Hideo Yagita, Eric Tartour, Julien Taieb, Magali Terme, Thibault Voron, Orianne Colussi, Elie Marcheteau, Simon Pernot, Mevyn Nizard, Anne-Laure Pointet, Sabrina Latreche, Sonia Bergaya, Nadine Benhamouda, Corinne Tanchot, Christian Stockmann, Pierre Combe, Anne Berger, Franck Zinzindohoue, Hideo Yagita, Eric Tartour, Julien Taieb, Magali Terme
Abstract
Immune escape is a prerequisite for tumor development. To avoid the immune system, tumors develop different mechanisms, including T cell exhaustion, which is characterized by expression of immune inhibitory receptors, such as PD-1, CTLA-4, Tim-3, and a progressive loss of function. The recent development of therapies targeting PD-1 and CTLA-4 have raised great interest since they induced long-lasting objective responses in patients suffering from advanced metastatic tumors. However, the regulation of PD-1 expression, and thereby of exhaustion, is unclear. VEGF-A, a proangiogenic molecule produced by the tumors, plays a key role in the development of an immunosuppressive microenvironment. We report in the present work that VEGF-A produced in the tumor microenvironment enhances expression of PD-1 and other inhibitory checkpoints involved in CD8(+) T cell exhaustion, which could be reverted by anti-angiogenic agents targeting VEGF-A-VEGFR. In view of these results, association of anti-angiogenic molecules with immunomodulators of inhibitory checkpoints may be of particular interest in VEGF-A-producing tumors.
© 2015 Voron et al.
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References
- Adotevi O., Pere H., Ravel P., Haicheur N., Badoual C., Merillon N., Medioni J., Peyrard S., Roncelin S., Verkarre V., et al. . 2010. 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 10.1097/CJI.0b013e3181f4c208
- Appay V., Jandus C., Voelter V., Reynard S., Coupland S.E., Rimoldi D., Lienard D., Guillaume P., Krieg A.M., Cerottini J.-C., et al. . 2006. New generation vaccine induces effective melanoma-specific CD8+ T cells in the circulation but not in the tumor site. J. Immunol. 177:1670–1678 10.4049/jimmunol.177.3.1670
- Baitsch L., Baumgaertner P., Devêvre E., Raghav S.K., Legat A., Barba L., Wieckowski S., Bouzourene H., Deplancke B., Romero P., et al. . 2011. Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J. Clin. Invest. 121:2350–2360 10.1172/JCI46102
- Blackburn S.D., Shin H., Haining W.N., Zou T., Workman C.J., Polley A., Betts M.R., Freeman G.J., Vignali D.A.A., and Wherry E.J.. 2009. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10:29–37 10.1038/ni.1679
- Cao M., Xu Y., Youn J.I., Cabrera R., Zhang X., Gabrilovich D., Nelson D.R., and Liu C.. 2011. Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. Lab. Invest. 91:598–608 10.1038/labinvest.2010.205
- Dubreuil P., Letard S., Ciufolini M., Gros L., Humbert M., Castéran N., Borge L., Hajem B., Lermet A., Sippl W., et al. . 2009. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS ONE. 4:e7258 10.1371/journal.pone.0007258
- Duraiswamy J., Kaluza K.M., Freeman G.J., and Coukos G.. 2013. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 73:3591–3603 10.1158/0008-5472.CAN-12-4100
- Finke J.H., Rini B., Ireland J., Rayman P., Richmond A., Golshayan A., Wood L., Elson P., Garcia J., Dreicer R., and Bukowski R.. 2008. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin. Cancer Res. 14:6674–6682 10.1158/1078-0432.CCR-07-5212
- Gabrilovich D.I., Chen H.L., Girgis K.R., Cunningham H.T., Meny G.M., Nadaf S., Kavanaugh D., and Carbone D.P.. 1996. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2:1096–1103 10.1038/nm1096-1096
- Gavalas N.G., Tsiatas M., Tsitsilonis O., Politi E., Ioannou K., Ziogas A.C., Rodolakis A., Vlahos G., Thomakos N., Haidopoulos D., et al. . 2012. VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2. Br. J. Cancer. 107:1869–1875 10.1038/bjc.2012.468
- Gibson H.M., Hedgcock C.J., Aufiero B.M., Wilson A.J., Hafner M.S., Tsokos G.C., and Wong H.K.. 2007. Induction of the CTLA-4 gene in human lymphocytes is dependent on NFAT binding the proximal promoter. J. Immunol. 179:3831–3840 10.4049/jimmunol.179.6.3831
- Hamid O., Robert C., Daud A., Hodi F.S., Hwu W.-J., Kefford R., Wolchok J.D., Hersey P., Joseph R.W., Weber J.S., et al. . 2013. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369:134–144 10.1056/NEJMoa1305133
- Huang Y., Chen X., Dikov M.M., Novitskiy S.V., Mosse C.A., Yang L., and Carbone D.P.. 2007. Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood. 110:624–631 10.1182/blood-2007-01-065714
- Ko J.S., Zea A.H., Rini B.I., Ireland J.L., Elson P., Cohen P., Golshayan A., Rayman P.A., Wood L., Garcia J., et al. . 2009. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin. Cancer Res. 15:2148–2157 10.1158/1078-0432.CCR-08-1332
- Le Roy C., Deglesne P.-A., Chevallier N., Beitar T., Eclache V., Quettier M., Boubaya M., Letestu R., Lévy V., Ajchenbaum-Cymbalista F., and Varin-Blank N.. 2012. The degree of BCR and NFAT activation predicts clinical outcomes in chronic lymphocytic leukemia. Blood. 120:356–365 10.1182/blood-2011-12-397158
- Liu Z.-J., Shirakawa T., Li Y., Soma A., Oka M., Dotto G.P., Fairman R.M., Velazquez O.C., and Herlyn M.. 2003. Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol. Cell. Biol. 23:14–25 10.1128/MCB.23.1.14-25.2003
- Oestreich K.J., Yoon H., Ahmed R., and Boss J.M.. 2008. NFATc1 regulates PD-1 expression upon T cell activation. J. Immunol. 181:4832–4839 10.4049/jimmunol.181.7.4832
- Ozao-Choy J., Ma G., Kao J., Wang G.X., Meseck M., Sung M., Schwartz M., Divino C.M., Pan P.-Y., and Chen S.-H.. 2009. 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 10.1158/0008-5472.CAN-08-4709
- Sakuishi K., Apetoh L., Sullivan J.M., Blazar B.R., Kuchroo V.K., and Anderson A.C.. 2010. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207:2187–2194 10.1084/jem.20100643
- Schreiber R.D., Old L.J., and Smyth M.J.. 2011. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 331:1565–1570 10.1126/science.1203486
- Schweighofer B., Testori J., Sturtzel C., Sattler S., Mayer H., Wagner O., Bilban M., and Hofer E.. 2009. The VEGF-induced transcriptional response comprises gene clusters at the crossroad of angiogenesis and inflammation. Thromb. Haemost. 102:544–554.
- Stockmann C., Doedens A., Weidemann A., Zhang N., Takeda N., Greenberg J.I., Cheresh D.A., and Johnson R.S.. 2008. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature. 456:814–818 10.1038/nature07445
- Terme M., Pernot S., Marcheteau E., Sandoval F., Benhamouda N., Colussi O., Dubreuil O., Carpentier A.F., Tartour E., and Taieb J.. 2013. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 73:539–549 10.1158/0008-5472.CAN-12-2325
- Topalian S.L., Hodi F.S., Brahmer J.R., Gettinger S.N., Smith D.C., McDermott D.F., Powderly J.D., Carvajal R.D., Sosman J.A., Atkins M.B., et al. . 2012. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366:2443–2454 10.1056/NEJMoa1200690
- Wherry E.J.2011. T cell exhaustion. Nat. Immunol. 12:492–499 10.1038/ni.2035
- Wherry E.J., Ha S.-J., Kaech S.M., Haining W.N., Sarkar S., Kalia V., Subramaniam S., Blattman J.N., Barber D.L., and Ahmed R.. 2007. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 27:670–684 10.1016/j.immuni.2007.09.006
- Whiteside T.L., and Parmiani G.. 1994. Tumor-infiltrating lymphocytes: their phenotype, functions and clinical use. Cancer Immunol. Immunother. 39:15–21 10.1007/BF01517175
- Woo S.-R., Turnis M.E., Goldberg M.V., Bankoti J., Selby M., Nirschl C.J., Bettini M.L., Gravano D.M., Vogel P., Liu C.L., et al. . 2012. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72:917–927 10.1158/0008-5472.CAN-11-1620
- Yamazaki T., Akiba H., Koyanagi A., Azuma M., Yagita H., and Okumura K.. 2005. Blockade of B7-H1 on macrophages suppresses CD4+ T cell proliferation by augmenting IFN-gamma-induced nitric oxide production. J. Immunol. 175:1586–1592 10.4049/jimmunol.175.3.1586
- Ziogas A.C., Gavalas N.G., Tsiatas M., Tsitsilonis O., Politi E., Terpos E., Rodolakis A., Vlahos G., Thomakos N., Haidopoulos D., et al. . 2012. VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor Type 2. Int. J. Cancer. 130:857–864 10.1002/ijc.26094
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