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Targeting the Effector Site with IFN-β-Inducing TLR Ligands Reactivates Tumor-Resident CD8 T Cell Responses to Eradicate Established Solid Tumors¹

Andrew J. Currie^2,3,*, Robbert G. van der Most^2,*, Steve A. Broomfield, Amy C. Prosser^*, Michael G. Tovey and Bruce W. S. Robinson^*,

^* National Research Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia; and Laboratory of Viral Oncology, Institut André Lwoff, Villejuif, France

Effective antitumor CD8 T cell responses may be activated by directly targeting the innate immune system within tumors. We investigated this response by injecting a range of TLR agonists into established tumors using a mouse model of malignant mesothelioma stably transduced with the hemagglutinin (HA) gene as a marker Ag (AB1-HA). Persistent delivery of the dsRNA mimetic poly(I:C) into established AB1-HA tumors resulted in complete tumor resolution in 40% of mice, with the remaining mice also showing a significant delay in tumor progression. Experiments in athymic nude mice along with CD8 depletion and IFN-β blocking studies revealed that tumor resolution required both CD8 T cells and type I IFN induction, and was associated with local changes in MHC class I expression. Surprisingly, however, tumor resolution was not associated with systemic dissemination or tumor infiltration of effector CD8 T cells. Instead, the antitumor response was critically dependent on the reactivation of tumor-resident CD8 T cell responses. These studies suggest that, once reactivated, pre-existing local CD8 T cell responses are sufficient to resolve established tumors and that in situ type I IFN is a determining factor.

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 Health & Medical Research Council of Australia.

² A.J.C. and R.G.v.d.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Andrew J. Currie, National Research Centre for Asbestos Related Diseases, 4th Floor G Block, QEII Medical Centre, Verdun St. Nedlands, Perth 6009, Western Australia. E-mail address: ajcurrie{at}cyllene.uwa.edu.au

⁴ Abbreviations used in this paper: DC, dendritic cell; HA, hemagglutinin; poly(I:C), polyinosinic-polycytidylic acid.