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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 10/2009

01-10-2009 | Original Article

Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor β

Authors: Taku Nagai, Masashi Tanaka, Yasuhiro Tsuneyoshi, Baohui Xu, Sara A. Michie, Kazuhisa Hasui, Hirofumi Hirano, Kazunori Arita, Takami Matsuyama

Published in: Cancer Immunology, Immunotherapy | Issue 10/2009

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Abstract

Tumor-associated macrophages (TAMs) are frequently found in glioblastomas and a high degree of macrophage infiltration is associated with a poor prognosis for glioblastoma patients. However, it is unclear whether TAMs in glioblastomas promote tumor growth. In this study, we found that folate receptor β (FRβ) was expressed on macrophages in human glioblastomas and a rat C6 glioma implanted subcutaneously in nude mice. To target FRβ-expressing TAMs, we produced a recombinant immunotoxin consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse FRβ monoclonal antibody and Pseudomonas exotoxin A. Injection of the immunotoxin into C6 glioma xenografts in nude mice significantly depleted TAMs and reduced tumor growth. The immunotoxin targeting FRβ-expressing macrophages will provide a therapeutic tool for human glioblastomas.
Literature
1.
Bacman D, Merkel S, Croner R, Papadopoulos T, Brueckl W, Dimmler A (2007) TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study. BMC Cancer 7:156PubMedCrossRef
2.
Bolat F, Kayaselcuk F, Nursal TZ, Yagmurdur MC, Bal N, Demirhan B (2006) Microvessel density, VEGF expression, and tumor-associated macrophages in breast tumors: correlations with prognostic parameters. J Exp Clin Cancer Res 25:365–372PubMed
3.
Chen JJ, Lin YC, Yao PL, Yuan A, Chen HY, Shun CT, Tsai MF, Chen CH, Yang PC (2005) Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol 23:953–964PubMedCrossRef
4.
Deininger MH, Meyermann R, Schluesener HJ (2003) Expression and release of CD14 in astrocytic brain tumors. Acta Neuropathol 106:271–277PubMedCrossRef
5.
Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196:254–265PubMedCrossRef
6.
Allavena P, Sica A, Solinas G, Porta C, Mantovani A (2007) The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 66:1–9PubMedCrossRef
7.
Porta C, Subhra Kumar B, Larghi P, Rubino L, Mancino A, Sica A (2007) Tumor promotion by tumor-associated macrophages. Adv Exp Med Biol 604:67–86PubMedCrossRef
8.
Yao Y, Kubota T, Sato K, Kitai R (2001) Macrophage infiltration-associated thymidine phosphorylase expression correlates with increased microvessel density and poor prognosis in astrocytic tumors. Clin Cancer Res 7:4021–4026PubMed
9.
Tsutsui S, Yasuda K, Suzuki K, Tahara K, Higashi H, Era S (2005) Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density. Oncol Rep 14:425–431PubMed
10.
Ueno T, Toi M, Saji H, Muta M, Bando H, Kuroi K, Koike M, Inadera H, Matsushima K (2000) Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res 6:3282–3289PubMed
11.
Lin EY, Pollard JW (2004) Macrophages: modulators of breast cancer progression. Novartis Found Symp 256:158–168PubMedCrossRef
12.
Lewis CE, De Palma M, Naldini L (2007) Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 67:8429–8432PubMedCrossRef
13.
Gallina G, Dolcetti L, Serafini P, De Santo C, Marigo I, Colombo MP, Basso G, Brombacher F, Borrello I, Zanovello P, Bicciato S, Bronte V (2006) Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest 116:2777–2790PubMedCrossRef
14.
Bak SP, Walters JJ, Takeya M, Conejo-Garcia JR, Berwin BL (2007) Scavenger receptor-A-targeted leukocyte depletion inhibits peritoneal ovarian tumor progression. Cancer Res 67:4783–4789PubMedCrossRef
15.
Kagaya T, Nakamoto Y, Sakai Y, Tsuchiyama T, Yagita H, Mukaida N, Kaneko S (2006) Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer. Cancer Gene Ther 13:357–366PubMedCrossRef
16.
Gazzaniga S, Bravo AI, Guglielmotti A, van Rooijen N, Maschi F, Vecchi A, Mantovani A, Mordoh J, Wainstok R (2007) Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. J Invest Dermatol 127:2031–2041PubMedCrossRef
17.
Nagayoshi R, Nagai T, Matsushita K, Sato K, Sunahara N, Matsuda T, Nakamura T, Komiya S, Onda M, Matsuyama T (2005) Effectiveness of anti-folate receptor-beta antibody conjugated with truncated Pseudomonas exotoxin in the targeting of rheumatoid arthritis synovial macrophages. Arthritis Rheum 52:2666–2675PubMedCrossRef
18.
Nagai T, Tanaka M, Tsuneyoshi Y, Matsushita K, Sunahara N, Matsuda T, Yoshida H, Komiya S, Onda M, Matsuyama T (2006) In vitro and in vivo efficacy of a recombinant immunotoxin against folate receptor beta on the activation and proliferation of rheumatoid arthritis synovial cells. Arthritis Rheum 54:3126–3134PubMedCrossRef
19.
Giometto B, Bozza F, Faresin F, Alessio L, Mingrino S, Tavolato B (1996) Immune infiltrates and cytokines in gliomas. Acta Neurochir (Wien) 138:50–56CrossRef
20.
Tynninen O, Aronen HJ, Ruhala M, Paetau A, Von Boguslawski K, Salonen O, Jääskeläinen J, Paavonen T (1999) MRI enhancement and microvascular density in gliomas. Correlation with tumor cell proliferation. Invest Radiol 34:427–434PubMedCrossRef
21.
Gabizon A, Horowitz AT, Goren D, Tzemach D, Mandelbaum-Shavit F, Qazen MM, Zalipsky S (1999) Targeting folate receptor with folate linked to extremities of poly(ethylene glycol)-grafted liposomes: in vitro studies. Bioconjug Chem 10:289–298PubMedCrossRef
22.
Stefanik DF, Fellows WK, Rizkalla LR, Rizkalla WM, Stefanik PP, Deleo AB, Welch WC (2001) Monoclonal antibodies to vascular endothelial growth factor (VEGF) and the VEGF receptor, FLT-1, inhibit the growth of C6 glioma in a mouse xenograft. J Neurooncol 55:91–100PubMedCrossRef
23.
Matsushita N, Kashiwagi M, Wait R, Nagayoshi R, Nakamura M, Matsuda T, Hogger P, Guyre PM, Nagase H, Matsuyama T (2002) Elevated levels of soluble CD163 in sera and fluids from rheumatoid arthritis patients and inhibition of the shedding of CD163 by TIMP-3. Clin Exp Immunol 130:156–161PubMedCrossRef
24.
Wesseling P, van der Laak JA, Link M, Teepen HL, Ruiter DJ (1998) Quantitative analysis of microvascular changes in diffuse astrocytic neoplasms with increasing grade of malignancy. Hum Pathol 29:352–358PubMedCrossRef
25.
Hasui K, Takatsuka T, Sakamoto R, Matsushita S, Tsuyama S, Izumo S, Murata F (2003) Double autoimmunostaining with glycine treatment. J Histochem Cytochem 51:1169–1176PubMed
26.
Ghassabeh GH, De Baetselier P, Brys L, Noël W, Van Ginderachter JA, Meerschaut S, Beschin A, Brombacher F, Raes G (2006) Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions. Blood 108:575–583PubMedCrossRef
27.
Grobben B, De Deyn PP, Slegers H (2002) Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion. Cell Tissue Res 310:257–270PubMedCrossRef
28.
Kirsch M, Strasser J, Allende R, Bello L, Zhang J, Black PM (1998) Angiostatin suppresses malignant glioma growth in vivo. Cancer Res 58:4654–4659PubMed
29.
Komohara Y, Ohnishi K, Kuratsu J, Takeya M (2008) Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 216:15–24PubMedCrossRef
30.
Turk MJ, Waters DJ, Low PS (2004) Folate-conjugated liposomes preferentially target macrophages associated with ovarian carcinoma. Cancer Lett 213(2):165–172PubMedCrossRef
31.
Pastan I, Hassan R, FitzGerald DJ, Kreitman RJ (2007) Immunotoxin treatment of cancer. Annu Rev Med 58:221–237PubMedCrossRef
32.
De Lorenzo C, D’Alessio G (2008) From immunotoxins to immunoRNases. Curr Pharm Biotechnol 9(3):210–214PubMedCrossRef
33.
Rainov NG, Gorbatyuk K, Heidecke V (2008) Clinical trials with intracerebral convection-enhanced delivery of targeted toxins in malignant glioma. Rev Recent Clin Trials 3:2–9PubMedCrossRef
34.
35.
Nishie A, Ono M, Shono T et al (1999) Macrophage infiltration and heme oxygenase–1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res 5:1107–1113PubMed
36.
Doblas S, Saunders D, Kshirsagar P, Pye Q, Oblander J, Gordon B, Kosanke S, Floyd RA, Towner RA (2008) Phenyl-tert-butylnitrone induces tumor regression and decreases angiogenesis in a C6 rat glioma model. Free Radic Biol Med 44:63–72PubMedCrossRef
37.
Galarneau H, Villeneuve J, Gowing G, Julien JP, Vallières L (2007) Increased glioma growth in mice depleted of macrophages. Cancer Res 67:8874–8881PubMedCrossRef
38.
Dirkx AE, Oude Egbrink MG, Wagstaff J, Griffioen AW (2006) Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J Leukoc Biol 80:1183–1196PubMedCrossRef
39.
Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, Ferrara N (2007) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b + Gr1 + myeloid cells. Nat Biotechnol 25:911–920PubMedCrossRef
Metadata
Title
Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor β
Authors
Taku Nagai
Masashi Tanaka
Yasuhiro Tsuneyoshi
Baohui Xu
Sara A. Michie
Kazuhisa Hasui
Hirofumi Hirano
Kazunori Arita
Takami Matsuyama
Publication date
01-10-2009
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 10/2009
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-009-0667-x

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