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Open Access 01-06-2019 | Glioblastoma | Original Article

Absolute numbers of regulatory T cells and neutrophils in corticosteroid-free patients are predictive for response to bevacizumab in recurrent glioblastoma patients

Authors: Véronique Quillien, Antoine F. Carpentier, Alain Gey, Tony Avril, Eric Tartour, Floraly Sejalon, Boris Campillo-Gimenez, Elodie Vauleon

Published in: Cancer Immunology, Immunotherapy | Issue 6/2019

Abstract

Bevacizumab (Bv) remains frequently prescribed in glioblastoma (GBM) patients, especially at recurrence. We conducted a prospective clinical trial with 29 recurrent GBM patients treated with Bv alone with a longitudinal follow-up of different circulating immune cells [complete blood count, myeloid-derived suppressor cells (MDSCs), classical, intermediate, non-classical and Tie2 monocytes, VEGFR1+ and regulatory T cells (Treg)]. We observed a significant increase for leucocytes, neutrophils, eosinophils and classical monocytes and a decrease for the fraction of Treg during the treatment. The best prognostic values for survival under Bv were obtained for basal neutrophils and Treg. Counts below 3.9 G/L for neutrophils and above 0.011 G/L for Treg were associated with an overall survival of 17.5 and 19.9 months, respectively, as compared with 5.4 and 5.6 months, respectively, for counts above and below these cutoffs (p = 0.004 and p < 0.001). No prognostic impact was observed for neutrophils in a retrospective cohort of 26 patients treated with nitrosoureas alone. In another retrospective validation cohort of 61 GBM patients treated at recurrence with a Bv-containing regimen, an interaction was observed between neutrophils and corticosteroid intake. The predictive value of neutrophils on survival under Bv was lost in patients treated with corticosteroids, when steroid-free patients with a low neutrophil count had a particularly long median survival of 3.4 years. These two simply accessible criteria (basal neutrophils and steroid intake) could be used to reserve this relatively costly treatment for patients likely to be the most responsive to Bv and prevent unnecessary side effects in others.

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Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740CrossRefPubMed

Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745CrossRefPubMed

Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ (2014) Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol 15:943–953. https://doi.org/10.1016/S1470-2045(14)70314-6 CrossRefPubMed

Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, Brandes AA, Taal W, Domont J, Idbaih A, Campone M, Clement PM, Stupp R, Fabbro M, Le Rhun E, Dubois F, Weller M, von Deimling A, Golfinopoulos V, Bromberg JC, Platten M, Klein M, van den Bent MJ (2017) Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 377:1954–1963. https://doi.org/10.1056/NEJMoa1707358 CrossRefPubMed

Rana P, Pritchard KI, Kerbel R (2017) Plasma vascular endothelial growth factor as a predictive biomarker: door closed? Eur J Cancer 70:143–145. https://doi.org/10.1016/j.ejca.2016.11.002 CrossRefPubMed

Baumgarten P, Blank AE, Franz K, Hattingen E, Dunst M, Zeiner P, Hoffmann K, Bahr O, Mader L, Goeppert B, Machein M, Seifert V, Steinbach JP, Plate KH, Harter PN, Mittelbronn M (2016) Differential expression of vascular endothelial growth factor A, its receptors VEGFR-1, -2, and -3 and co-receptors neuropilin-1 and -2 does not predict bevacizumab response in human astrocytomas. Neuro Oncol 18:173–183. https://doi.org/10.1093/neuonc/nov288 CrossRefPubMed

Erdem-Eraslan L, van den Bent MJ, Hoogstrate Y, Naz-Khan H, Stubbs A, van der Spek P, Bottcher R, Gao Y, de Wit M, Taal W, Oosterkamp HM, Walenkamp A, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, van der Holt B, Vernhout RM, Sillevis Smitt PA, Kros JM, French PJ (2016) Identification of patients with recurrent glioblastoma who may benefit from combined bevacizumab and CCNU therapy: a report from the BELOB trial. Cancer Res 76:525–534. https://doi.org/10.1158/0008-5472.CAN-15-0776 CrossRefPubMed

Laffaire J, Di Stefano AL, Chinot O, Idbaih A, Gallego Perez-Larraya J, Marie Y, Vintonenko N, Boisselier B, Farina P, Delattre JY, Figarella-Branger D, Honnorat J, Sanson M, Ducray F (2014) An ANOCEF genomic and transcriptomic microarray study of the response to irinotecan and bevacizumab in recurrent glioblastomas. Biomed Res Int 2014:282815. https://doi.org/10.1155/2014/282815 CrossRefPubMedPubMedCentral

Hayes J, Thygesen H, Gregory W, Westhead DR, French PJ, Van Den Bent MJ, Lawler SE, Short SC (2016) A validated microRNA profile with predictive potential in glioblastoma patients treated with bevacizumab. Mol Oncol 10:1296–1304. https://doi.org/10.1016/j.molonc.2016.06.004 CrossRefPubMedPubMedCentral

10.

Urup T, Michaelsen SR, Olsen LR, Toft A, Christensen IJ, Grunnet K, Winther O, Broholm H, Kosteljanetz M, Issazadeh-Navikas S, Poulsen HS, Lassen U (2016) Angiotensinogen and HLA class II predict bevacizumab response in recurrent glioblastoma patients. Mol Oncol 10:1160–1168. https://doi.org/10.1016/j.molonc.2016.05.005 CrossRefPubMedPubMedCentral

11.

Rivera LB, Meyronet D, Hervieu V, Frederick MJ, Bergsland E, Bergers G (2015) Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy. Cell Rep 11:577–591. https://doi.org/10.1016/j.celrep.2015.03.055 CrossRefPubMedPubMedCentral

12.

Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, Dubreuil O, Carpentier AF, Tartour E, Taieb J (2013) VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 73:539–549. https://doi.org/10.1158/0008-5472.CAN-12-2325 CrossRefPubMed

13.

Adotevi O, Pere H, Ravel P, Haicheur N, Badoual C, Merillon N, Medioni J, Peyrard S, Roncelin S, Verkarre V, Mejean A, Fridman WH, Oudard S, Tartour E (2010) A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother 33:991–998CrossRefPubMed

14.

Du Four S, Maenhout SK, Benteyn D, De Keersmaecker B, Duerinck J, Thielemans K, Neyns B, Aerts JL (2016) Disease progression in recurrent glioblastoma patients treated with the VEGFR inhibitor axitinib is associated with increased regulatory T cell numbers and T cell exhaustion. Cancer Immunol Immunother 65:727–740. https://doi.org/10.1007/s00262-016-1836-3 CrossRefPubMed

15.

Pitter KL, Tamagno I, Alikhanyan K, Hosni-Ahmed A, Pattwell SS, Donnola S, Dai C, Ozawa T, Chang M, Chan TA, Beal K, Bishop AJ, Barker CA, Jones TS, Hentschel B, Gorlia T, Schlegel U, Stupp R, Weller M, Holland EC, Hambardzumyan D (2016) Corticosteroids compromise survival in glioblastoma. Brain 139:1458–1471. https://doi.org/10.1093/brain/aww046 CrossRefPubMedPubMedCentral

16.

Nakagawa M, Terashima T, D’Yachkova Y, Bondy GP, Hogg JC, van Eeden SF (1998) Glucocorticoid-induced granulocytosis: contribution of marrow release and demargination of intravascular granulocytes. Circulation 98:2307–2313CrossRefPubMed

17.

Massena S, Christoffersson G, Vagesjo E, Seignez C, Gustafsson K, Binet F, Herrera Hidalgo C, Giraud A, Lomei J, Westrom S, Shibuya M, Claesson-Welsh L, Gerwins P, Welsh M, Kreuger J, Phillipson M (2015) Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans. Blood 126:2016–2026. https://doi.org/10.1182/blood-2015-03-631572 CrossRefPubMedPubMedCentral

18.

Liang J, Piao Y, Holmes L, Fuller GN, Henry V, Tiao N, de Groot JF (2014) Neutrophils promote the malignant glioma phenotype through S100A4. Clin Cancer Res 20:187–198. https://doi.org/10.1158/1078-0432.CCR-13-1279 CrossRefPubMed

19.

Sippel TR, White J, Nag K, Tsvankin V, Klaassen M, Kleinschmidt-DeMasters BK, Waziri A (2011) Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I. Clin Cancer Res 17:6992–7002. https://doi.org/10.1158/1078-0432.CCR-11-1107 CrossRefPubMed

20.

Marini O, Costa S, Bevilacqua D, Calzetti F, Tamassia N, Spina C, De Sabata D, Tinazzi E, Lunardi C, Scupoli MT, Cavallini C, Zoratti E, Tinazzi I, Marchetta A, Vassanelli A, Cantini M, Gandini G, Ruzzenente A, Guglielmi A, Missale F, Vermi W, Tecchio C, Cassatella MA, Scapini P (2017) Mature CD10(+) and immature CD10(−) neutrophils present in G-CSF-treated donors display opposite effects on T cells. Blood 129: 1343–1356. https://doi.org/10.1182/blood-2016-04-713206 CrossRefPubMed

21.

Gielen PR, Schulte BM, Kers-Rebel ED, Verrijp K, Bossman SA, Ter Laan M, Wesseling P, Adema GJ (2016) Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8/9 and arginase and suppress T cell function. Neuro Oncol 18:1253–1264. https://doi.org/10.1093/neuonc/now034 CrossRefPubMedPubMedCentral

22.

Raychaudhuri B, Rayman P, Ireland J, Ko J, Rini B, Borden EC, Garcia J, Vogelbaum MA, Finke J (2011) Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol 13:591–599. https://doi.org/10.1093/neuonc/nor042 CrossRefPubMedPubMedCentral

23.

Lopes M, Carvalho B, Vaz R, Linhares P (2018) Influence of neutrophil-lymphocyte ratio in prognosis of glioblastoma multiforme. J Neurooncol 136:173–180. https://doi.org/10.1007/s11060-017-2641-3 CrossRefPubMed

24.

Mason M, Maurice C, McNamara MG, Tieu MT, Lwin Z, Millar BA, Menard C, Laperriere N, Milosevic M, Atenafu EG, Mason W, Chung C (2017) Neutrophil–lymphocyte ratio dynamics during concurrent chemo-radiotherapy for glioblastoma is an independent predictor for overall survival. J Neurooncol 132:463–471. https://doi.org/10.1007/s11060-017-2395-y CrossRefPubMed

25.

Han S, Liu Y, Li Q, Li Z, Hou H, Wu A (2015) Pre-treatment neutrophil-to-lymphocyte ratio is associated with neutrophil and T-cell infiltration and predicts clinical outcome in patients with glioblastoma. BMC Cancer 15:617. https://doi.org/10.1186/s12885-015-1629-7 CrossRefPubMedPubMedCentral

26.

Alexiou GA, Vartholomatos E, Voulgaris S (2013) Prognostic value of neutrophil-to-lymphocyte ratio in patients with glioblastoma. J Neurooncol 115:521–522. https://doi.org/10.1007/s11060-013-1240-1 CrossRefPubMed

27.

Bertaut A, Truntzer C, Madkouri R, Kaderbhai CG, Derangere V, Vincent J, Chauffert B, Aubriot-Lorton MH, Farah W, Mourier KL, Boidot R, Ghiringhelli F (2016) Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma. Oncotarget. https://doi.org/10.18632/oncotarget.10898 CrossRefPubMedPubMedCentral

28.

Quillien V, Lavenu A, Ducray F, Joly MO, Chinot O, Fina F, Sanson M, Carpentier C, Karayan-Tapon L, Rivet P, Entz-Werle N, Legrain M, Zalcman EL, Levallet G, Escande F, Ramirez C, Chiforeanu D, Vauleon E, Figarella-Branger D (2016) Validation of the high-performance of pyrosequencing for clinical MGMT testing on a cohort of glioblastoma patients from a prospective dedicated multicentric trial. Oncotarget 7:61916–61929. https://doi.org/10.18632/oncotarget.11322 CrossRefPubMedPubMedCentral

29.

Badoual C, Hans S, Fridman WH, Brasnu D, Erdman S, Tartour E (2009) Revisiting the prognostic value of regulatory T cells in patients with cancer. J Clin Oncol 27:e5–e6 (author reply e7). https://doi.org/10.1200/JCO.2009.23.0680 CrossRefPubMed

30.

Shang B, Liu Y, Jiang SJ (2015) Prognostic value of tumor-infiltrating FoxP3⁺ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep 5:15179. https://doi.org/10.1038/srep15179 CrossRefPubMedPubMedCentral

31.

Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306. https://doi.org/10.1038/nrc3245 CrossRefPubMed

32.

Yue Q, Zhang X, Ye HX, Wang Y, Du ZG, Yao Y, Mao Y (2014) The prognostic value of Foxp3⁺ tumor-infiltrating lymphocytes in patients with glioblastoma. J Neurooncol 116:251–259. https://doi.org/10.1007/s11060-013-1314-0 CrossRefPubMed

33.

Thomas AA, Fisher JL, Rahme GJ, Hampton TH, Baron U, Olek S, Schwachula T, Rhodes CH, Gui J, Tafe LJ, Tsongalis GJ, Lefferts JA, Wishart H, Kleen J, Miller M, Whipple CA, de Abreu FB, Ernstoff MS, Fadul CE (2015) Regulatory T cells are not a strong predictor of survival for patients with glioblastoma. Neuro Oncol 17:801–809. https://doi.org/10.1093/neuonc/nou363 CrossRefPubMedPubMedCentral

34.

Han S, Zhang C, Li Q, Dong J, Liu Y, Huang Y, Jiang T, Wu A (2014) Tumour-infiltrating CD4(+) and CD8(+) lymphocytes as predictors of clinical outcome in glioma. Br J Cancer 110:2560–2568. https://doi.org/10.1038/bjc.2014.162 CrossRefPubMedPubMedCentral

35.

Voo KS, Foglietta M, Percivalle E, Chu F, Nattamai D, Harline M, Lee ST, Bover L, Lin HY, Baladandayuthapani V, Delgado D, Luong A, Davis RE, Kwak LW, Liu YJ, Neelapu SS (2014) Selective targeting of Toll-like receptors and OX40 inhibit regulatory T-cell function in follicular lymphoma. Int J Cancer 135:2834–2846. https://doi.org/10.1002/ijc.28937 CrossRefPubMedPubMedCentral

36.

Glowala-Kosinska M, Chwieduk A, Nieckula J, Sadus-Wojciechowska M, Grosicki S, Rusin A, Nowara E, Giebel S (2013) Association of circulating regulatory T cell number with the incidence and prognosis of diffuse large B-cell lymphoma. Eur J Haematol 91:122–128. https://doi.org/10.1111/ejh.12144 CrossRefPubMed

37.

Kotsakis A, Koinis F, Katsarou A, Gioulbasani M, Aggouraki D, Kentepozidis N, Georgoulias V, Vetsika EK (2016) Prognostic value of circulating regulatory T cell subsets in untreated non-small cell lung cancer patients. Sci Rep 6:39247. https://doi.org/10.1038/srep39247 CrossRefPubMedPubMedCentral

38.

Diaz RJ, Ali S, Qadir MG, De La Fuente MI, Ivan ME, Komotar RJ (2017) The role of bevacizumab in the treatment of glioblastoma. J Neurooncol 133:455–467. https://doi.org/10.1007/s11060-017-2477-x CrossRefPubMed

39.

Tabouret E, Boudouresque F, Barrie M, Matta M, Boucard C, Loundou A, Carpentier A, Sanson M, Metellus P, Figarella-Branger D, Ouafik L, Chinot O (2014) Association of matrix metalloproteinase 2 plasma level with response and survival in patients treated with bevacizumab for recurrent high-grade glioma. Neuro Oncol 16:392–399. https://doi.org/10.1093/neuonc/not226 CrossRefPubMed

Title: Absolute numbers of regulatory T cells and neutrophils in corticosteroid-free patients are predictive for response to bevacizumab in recurrent glioblastoma patients
Authors: Véronique Quillien
Antoine F. Carpentier
Alain Gey
Tony Avril
Eric Tartour
Floraly Sejalon
Boris Campillo-Gimenez
Elodie Vauleon
Publication date: 01-06-2019
Publisher: Springer Berlin Heidelberg
Keywords: Glioblastoma
Glioblastoma
Glioblastoma
Bevacizumab
Biomarkers
Published in: Cancer Immunology, Immunotherapy / Issue 6/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-019-02317-9

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