Plasmacytoid dendritic cell–derived type I interferon is crucial for the adjuvant activity of Toll-like receptor 7 agonists

Abstract

There is a high demand for the development of adjuvants that induce cytotoxic T lymphocytes, which are crucial for the elimination of intracellular pathogens and tumor cells. Toll-like receptor (TLR) agonists are prime candidates to fulfill this role because they induce innate immune activation and promote adaptive immune responses. The successful application of the TLR7 agonist R837 for treatment of basal cell carcinoma shows the potential for exploiting this pathway in tumor immunotherapy. Imidazoquinolines like R837 and stimulatory ssRNA oligonucleotides both trigger TLR7-mediated immune activation, but little is known about their comparative ability to promote immunity induction. We investigated differences in innate immune activation and adjuvant activity between the imidazoquinoline R848 and the ssRNA TLR7 agonist polyUs21. In contrast to R848, polyUs21 induced detectable levels of intracellular interferon-␣ (IFN-␣) in plasmacytoid dendritic cells (PDCs). In immunization studies, only polyUs21 led to robust priming of type 1 T helper cells and cytotoxic T lymphocytes, and it was more efficient in inducing antitumor immunity than R848. Notably, exogenous IFN-␣ augmented the adjuvant activity of R848, whereas depletion of PDC abrogated the adjuvanticity of polyUs21. This study, therefore, identifies sufficient IFN-␣ production by PDC as an important determinant of vaccine efficacy. (Blood. 2010;115:1949-1957 Introduction Cellular immune responses characterized by the induction of cytotoxic effector cells are crucial for therapeutic interventions in the context of tumor immunotherapy and for the induction of protective immunity against a variety of intracellular pathogens, such as the malaria parasite and HIV. A particular focus of novel vaccination strategies is the identification of adjuvants with the ability to skew adaptive immune responses toward a Th1 phenotype and thereby allow for the induction of cellular, in addition to humoral, immunity. 1 Synthetic mimics of pathogen-associated molecular patterns in general, and especially those mimicking virus presence, appear particularly potent in promoting the induction of cellular immunity and might therefore constitute powerful adjuvants. 2 Viral pathogen-associated molecular patterns can be detected by Toll-like receptors (TLRs) and cytoplasmic pattern recognition receptors. 3,4 The virus-sensing TLRs sample the contents of specialized endosomal compartments, where they detect bacterial and viral genomes, as well as viral replication intermediates. 3,4 Different classes of viral nucleic acids are detected by distinct TLRs with TLR3, TLR7/8, and TLR9 sensing dsRNA, ssRNA, and DNA, respectively. 3,4 Although various synthetic TLR agonists have been tried as adjuvants, 5 not many of them are approved for human use. In contrast, the TLR7/8 agonist R837 is approved for the topical treatment of genital warts, basal cell carcinoma, and bladder cancer. [6][7][8][9] Imidazoquinolines such as R837 and R848 originally were developed as small immune response modifiers ...

Trafficking properties of plasmacytoid dendritic cells in health and disease

“…Interestingly, a new cell population of CD11c + myeloid DCs endowed with tumoricidal potential was identified in these lesions [25]. The relevance of PDCs in cancer immunosurveillance has been recently shown in mice [68,69], where TLR9-activated PDCs lead to the regression of subcutaneous B16 melanoma tumors, by orchestrating the sequential activation of NK cells, MDCs and CD8 + T cells. The characterization of PDCs has been performed in a variety of human neoplasms [54,[70][71][72].…”

TLR7 Triggering with Polyuridylic Acid Promotes Cross-Presentation in CD8α+ Conventional Dendritic Cells by Enhancing Antigen Preservation and MHC Class I Antigen Permanence on the Dendritic Cell Surface

“…Recently, Rajagopal et al (22) and Wei et al (23) have demonstrated that other TLR7 ligands, such as a 21-mer of polyuridylic acid (polyUs21) and influenza-infected cell lines, respectively, can enhance cross-priming in DCs, generating strong cytotoxic immune responses. However, the molecular mechanisms underlying the stimulatory effect of TLR ligands on cross-presentation are not fully resolved.…”

“…The optimal ratio of polyU to DOTAP for complex formation was determined by dose titration (data not shown). It has been established that immunization with some TLR7 ligands, such as R848 (17), synthetic RNA oligonucleotides (35,36), influenza-infected allogeneic cell lines (23), or polyUs21 (22), led to potent CTL responses. To evaluate whether polyU is capable of acting as adjuvant for CTL response, mice were i.v.…”

“…Recent studies have highlighted the relevance of type I IFNs for the activation of CD8 + T cell responses, and in particular they have showed the crucial role for the adjuvant activity of TLR7 ligands (22,48). Therefore, to determine whether type I IFNs are playing a role in the adjuvant capacity of polyU, we conducted a CD8 + T cell proliferation assay using mice deficient in IFN-abR (IFNAR 2/2 ).…”

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

“…In addition, TLR7-mediated B cell proliferation, cytokine production, and costimulatory molecule expression are defective in IFNAR 2/2 mice (14). Many synthetic TLR7 ligands are currently under investigation as vaccine adjuvants (15) and antitumor agents (16), and type I IFN also enhances adjuvant activity of such ligands (17).…”