Oral Presentation Eradicate Cancer 2018

Targeting human CD141+ DC for cancer immunotherapy (#46)

Kristen Radford 1 , Tullet KM 2 , Masterman KA 1 , Pearson FE 1 , Walpole C 1 , Daraj G 1 , Leal Rojas IM 1 , Lahoud MH 2 , Haigh O 1
  1. Mater Research Institute-UQ, Brisbane, QLD, Australia
  2. Translational Research Institute, Brisbane, Queensland, Australia

DC are a heterogeneous cell population, with specialist subtypes driving specific immune responses. In mice, the cDC1 subset (also referred to as Batf3-dependent DC, XCR1+ DC, CD8+ DC in lymphoid tissues and CD103+ DC in peripheral tissues) is essential for the induction of tumour immune responses and for the efficacy of checkpoint inhibitor blockade and adoptive T cell immunotherapies. Vaccines that can deliver antigens (Ag) directly to dendritic cells (DCs) in vivo are more effective than cell-based therapies in mouse models and are promising approaches to translate to humans. CD141+ DC are the human cDC1 equivalent and specifically express the C-type lectin-like receptor CLEC9A that facilitates cross-presentation of dead cell Ag. NYESO1 and WT1 are well characterised, highly immunogenic tumour associated Ag (TAA) expressed by a broad array of tumour types. We developed a recombinant human chimaeric IgG4 antibody (Ab) specific for human CLEC9A genetically fused to NYESO1 or WT1. For comparison we developed TAA fusions with chimaeric IgG4 Ab specific for human DEC-205, which is expressed by many human leukocytes, and β-galactosidase as an irrelevant isotype control. CLEC9A-NYESO1 and CLEC9A-WT1 Abs retained their binding specificity for CD141+ DC. Following uptake of CLEC9A-WT1, CD141+ DC cross-presented a WT-1 HLA-A24-restricted epitope for recognition by specific cytotoxic T cells. Likewise, a HLA-A2-restricted NYESO1 epitope was cross-presented by CD141+ DC following uptake of CLEC9A-NYESO1. For both TAA, the CLEC9A Abs were more efficient at delivery of Ag for cross-presentation than DEC-205 or isotype control Abs. Targeting TAA to human CD141+ DC using CLEC9A Ab is therefore an attractive strategy to induce or boost tumour immune responses.