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Cell-Associated Double-Stranded RNA Enhances Antitumor Activity through the Production of Type I IFN¹

Sara McBride^*, Kasper Hoebe, Philippe Georgel and Edith Janssen^2,*

^* La Jolla Institute for Allergy and Immunology, Developmental Immunology, La Jolla, CA 92037; and The Scripps Research Institute, Department of Immunology, La Jolla, CA 92037

The efficacy of tumor cell vaccination largely depends on the maturation and activation status of the dendritic cell. Here we investigated the ability of soluble and tumor cell-associated dsRNA to serve as an adjuvant in the induction of protective adaptive antitumor responses. Our data showed that cell-associated dsRNA, but not soluble dsRNA, enhanced both tumor-specific CD8⁺ and CD4⁺ T cell responses. The cell-associated dsRNA increased the clonal burst of tumor-specific CD8⁺ T cells and endowed them with an enhanced capacity for expansion upon a secondary encounter with tumor Ags, even when the CD8⁺ T cells were primed in the absence of CD4⁺ T cell help. The adjuvant effect of cell-associated dsRNA was fully dependent on the expression of TLR3 by the APCs and their subsequent production of type I IFNs, as the adjuvant effect of cell-associated dsRNA was completely abrogated in mice deficient in TLR3 or type I IFN signaling. Importantly, treatment with dsRNA-associated tumor cells increased the number of tumor-infiltrating lymphocytes and enhanced the survival of tumor-bearing mice. The data from our studies suggest that using cell-associated dsRNA as a tumor vaccine adjuvant may be a suitable strategy for enhancing vaccine efficacy for tumor cell therapy in cancer patients.

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 Leukemia and Lymphoma Society Career Development Award 3248-05 (to E.J.).

² Address correspondence and reprint requests to Dr. Edith Janssen, La Jolla Institute for Allergy and Immunology, Developmental Immunology 1B, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: EJanssen{at}liai.org

³ Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; PKR, protein kinase R; poly(I:C), polyinosinic-polycytidylic acid. RIG-I, retinoic acid-inducible gene I; TIL, tumor-infiltrating lymphocyte.

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