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Toll-like Receptors 3 and 7 Agonists Enhance Tumor Cell Lysis by Human T Cells

¹ Institute of Immunology, ² Department of Gynecology, and ³ First Department of Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany

Requests for reprints: Daniela Wesch, Institute of Immunology, UK S-H, Campus Kiel, Arnold-Heller Strasse 3, Haus 17, D-24105 Kiel, Germany. Phone: 49-431-5973379; Fax: 49-431-5973335; E-mail: wesch{at}immunologie.uni-kiel.de.

Toll-like receptor (TLR) agonists are considered adjuvants in clinical trials of cancer immunotherapy. Here, we investigated the modulation of T cell–mediated tumor cell lysis by TLR ligands. T-cell cytotoxicity and granzyme A/B production were enhanced after pretreatment of tumor cells with TLR3 [poly(I:C)] or TLR7 ligand (imiquimod). We examined TLR3- and TLR7-expressing pancreatic adenocarcinomas, squamous cell carcinomas of head and neck and lung carcinomas. Poly(I:C) treatment of pancreatic adenocarcinomas followed by coculture with T cells resulted in an upregulation of CD54 on the tumor cells. The interaction of CD54 and the corresponding ligand CD11a/CD18 expressed on T cells is responsible for triggering effector function in T cells. Moreover, treatment with imiquimod downregulated MHC class I molecules on tumor cells possibly resulting in a reduced binding affinity for inhibitory receptor NKG2A expressed on T cells. These results indicate that TLR3 or TLR7 ligand stimulation of tumor cells enhances the cytotoxic activity of expanded T cells of cancer patients in vitro. [Cancer Res 2009;69(22):8710–7]

Key Words: human • T cells • cytotoxicity • poly(I:C) • imiquimod