Cell-associated double-stranded RNA enhances antitumor activity through the production of type I IFN.
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.
McBride
Sara
S
La Jolla Institute for Allergy and Immunology, Developmental Immunology 1B, 9420 Athena Circle, La Jolla, CA 92037, USA.
Hoebe
Kasper
K
Georgel
Philippe
P
Janssen
Edith
E
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D007370:Interferon Type I / Q000096:biosynthesis*; D008212:Lymphocyte Depletion; D051379:Mice; D008817:Mice, Mutant Strains; D012330:RNA, Double-Stranded / Q000627:therapeutic use*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D013945:Thymoma / Q000188:drug therapy* / Q000276:immunology; D013953:Thymus Neoplasms / Q000188:drug therapy* / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000235:genetics
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D007370:Interferon Type I; D012330:RNA, Double-Stranded; D051196:Toll-Like Receptor 3; D053633:Receptor, Interferon alpha-beta