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Combined Triggering of Dendritic Cell Receptors Results in Synergistic Activation and Potent Cytotoxic Immunity¹

James W. Wells^*, Christopher J. Cowled^*, Farzin Farzaneh and Alistair Noble^2,*

^* Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, King’s College London, Guy’s Hospital, and Department of Haematological and Molecular Medicine, King’s College London, Rayne Institute, London, United Kingdom

Elimination of malignant cells and intracellular infections involves collaboration between CTLs and Th1 inflammation. Dendritic cells drive this response via costimulation and cytokines. We have defined key signals required for the exponential expansion of specific CD8⁺ T cells in vivo in mice. Immunization with two or more TLR agonists, anti-CD40, IFN-, and surfactant were sufficient to drive unprecedented levels of CD8 response to peptide or protein Ag and highly polarized Th1 CD4 responses. CD40 signaling was required for CD8 expansion but could be provided by a concomitant CD4 Th response in place of anti-CD40. Triggering of these pathways activated migration and activation of myeloid and plasmacytoid dendritic cells and secretion of IL-12. Cross-presentation can thus be exploited to induce potent cytotoxic responses and long-term memory to peptide/protein Ags. When combined with a tumor-associated peptide from tyrosinase-related protein 2, our combined adjuvant approach effectively halted tumor growth in an in vivo melanoma model and was more effective than anti-CD40 and a single TLR agonist. Antitumor immunity was associated with long-lived effector memory CD8 cells specific for the naturally processed and presented tumor Ag, and tumor protection was partially but not entirely dependent on CD8 T cells. This flexible strategy is more effective than existing adjuvants and provides a technological platform for rapid vaccine development.

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 by Asthma UK and King’s College London.

² Address correspondence and reprint requests to Dr. Alistair Noble, Department of Asthma, Allergy and Respiratory Science, Fifth Floor, Tower Wing, Guy’s Hospital, London SE1 9RT, U.K. E-mail address: alistair.noble{at}kcl.ac.uk

³ Abbreviations used in this paper: DC, dendritic cell; CASAC, combined adjuvant for synergistic activation of cellular immunity; CD40L, CD40 ligand; i.d., intradermal(ly); KLH, keyhole limpet hemocyanin; LN, lymph node; mDC, myeloid DC; MPL, monophosphoryl lipid A; Pam₃CSK₄, (S)-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys₄-OH, 3HCl; pDC, plasmacytoid DC; polyI:C, polyinosinic:polycytidylic acid; TDM, trehalose 6,6'-dimycolate; TRP-2, tyrosinase-related protein 2; VSV, vesicular stomatitis virus.