Activation of human CD141⁺ and CD1c⁺ dendritic cells in vivo with combined TLR3 and TLR7/8 ligation

Abstract

Mice reconstituted with human hematopoietic stem cells are valuable models to study aspects of the human immune system in vivo. We describe a humanized mouse model (hu mice) in which fully functional human CD141 and CD1c myeloid and CD123 plasmacytoid dendritic cells (DC) develop from human cord blood CD34 cells in immunodeficient mice. CD141 DC are the human equivalents of murine CD8 /CD103 DC which are essential for the induction of tumor-inhibitory cytotoxic T lymphocyte responses, making them attractive targets to exploit for the development of new cancer immunotherapies. We used CD34 -engrafted NSG-A2 mice to investigate activation of DC subsets by synthetic dsRNA or ssRNA analogs polyinosinic-polycytidylic acid/poly I:C and Resiquimod/R848, agonists for TLR3 and TLR8, respectively, both of which are expressed by CD141 DC. Injection of hu mice with these agonists resulted in upregulation of costimulatory molecules CD80, CD83 and CD86 by CD141 and CD1c DC alike, and their combination further enhanced expression of these molecules by both subsets. When combined, poly I:C and R848 enhanced serum levels of key cytokines associated with cross-presentation and the induction of cytotoxic T lymphocyte responses including IFN-α, IFN-β, IL-12 and CXCL10. These data advocate a combination of poly I:C and R848 TLR agonists as means of activating human DC for immunotherapy.

Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141+ dendritic cells to activate naïve and memory NY-ESO-1-specific CD8+ T cells

“… 45 46 Poly-ICLC (Hiltonol, a stabilized poly I:C derivative) is safe to administer in combination with DEC-205 targeting Ab (CDX-1401) and can induce humoral and cellular immunity in patients with cancer, making this adjuvant a logical choice to combine with CLEC9A-NY-ESO-1 in the clinic. 29 30 Although poly I:C combined with a TLR8 agonist can lead to even more potent activation of CD141 + DC in vivo, 46 this did not appear to confer any advantage to DEC-205 targeting in the clinical setting. 29 Whether Flt3L can enhance responses to vaccination with DEC-205 targeting and poly-ICLC is currently being evaluated in a phase II clinical trial in melanoma (NCT02129075) with early results demonstrating safety and tolerability.…”

Are Conventional Type 1 Dendritic Cells Critical for Protective Antitumor Immunity and How?

“…Considering their conserved specific expression pattern on mouse and human cDC1, and the very encouraging results obtained in mouse preclinical models, the CLEC9A and XCR1 receptors are the best candidates for Ag, or Ag+adjuvant cargo, delivery to human cDC1, using recombinant ligands (193, 194) or monoclonal antibodies. A combination of TLR3- and TLR8-specific agonists is desirable to promote an immunogenic maturation associated with the production of both IL-12 and IFN-β/λ (Table 6) (195). Targeting delivery of IFN-I activity to cDC1 is another very promising adjuvant based on the proof-of-principle published in mice (Tables 3, 5).…”

Functional Role of Dendritic Cell Subsets in Cancer Progression and Clinical Implications

“…Optimization of molecular pathways to boost DC anti-tumor activity, such as maturation, priming, and trafficking, is still required. Recent evidence suggests that cell maturation in cDC1-based vaccines can be optimized using TLR3 (poly I:C) and TLR8 (R848) stimulation [194,195]. To improve T cell priming ability, several antigen loading approaches were explored.…”