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* School of Medicine and Pharmacology, University of Western Australia, Perth, Australia;
National Centre for Asbestos Related Diseases, University of Western Australia, Perth, Australia;
Laboratory of Viral Oncology, Institut André Lwoff, Villejuif, France; and
Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
Topical application of tumors with the TLR7 agonist imiquimod is an effective adjunct treatment for a range of primary dermatological cancers. However, for therapy to be effective against a broad range of solid tumor types, it must promote a strong systemic antitumor response that targets metastases in addition to primary tumor. We therefore investigated the potential of locally delivered imiquimod to stimulate an effective systemic antitumor response in a murine model of malignant mesothelioma (AB1-HA) with primary and distal tumors (dual tumor). Persistent delivery of imiquimod into primary tumor significantly retarded tumor growth in all treated mice compared with vehicle control. This local antitumor immune response required both CD8 T cells and NK cells, but not CD4 T cells, and was reliant on type I IFN induction. In vivo CTL studies and Ly6A/E staining of lymphocytes suggested that local imiquimod treatment had indeed induced a systemic, Ag-specific CD8 response. However, notably this response was not sufficient to retard the growth of an untreated distal tumor. Because local imiquimod treatment did not induce significant CD4 T cell responses, we investigated the efficacy of combining imiquimod with agonistic CD40 Ab (as a surrogate for CD4 T cell help). Combination of locally delivered imiquimod with systemic anti-CD40 immunotherapy not only significantly enhanced the local antitumor response, with 30% complete resolution, but it was also effective at significantly retarding growth of distal tumor. These results demonstrate that antitumor responses induced by locally delivered TLR7 agonists can be harnessed systemically for treating distal tumor.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by the National Research Centre for Asbestos Related Diseases, as part of the Strategic Award by the National Health and Medical Research Council of Australia. M.J.S. was supported by a National Health and Medical Research Council Senior Principal Research Fellowship and Program grant.
2 Address correspondence and reprint requests to Dr. Andrew J. Currie, National Centre for Asbestos Related Diseases, 4th Floor G Block, QEII Medical Centre, Verdun Street, Nedlands, Perth, Western Australia 6009. E-mail address: ajcurrie{at}cyllene.uwa.edu.au
3 Abbreviations used in this paper: DC, dendritic cell; CBS, citrate-buffered saline; HA, hemagglutinin.
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  C. Bourquin, L. Schmidt, A.-L. Lanz, B. Storch, C. Wurzenberger, D. Anz, N. Sandholzer, R. Mocikat, M. Berger, H. Poeck, et al. Immunostimulatory RNA Oligonucleotides Induce an Effective Antitumoral NK Cell Response through the TLR7 J. Immunol., November 15, 2009; 183(10): 6078 - 6086. [Abstract] [Full Text] [PDF]
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