Dendritic cells (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 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. Targeting tumour-associated Ag (TAA) to human CD141+ DC using CLEC9A antibody (Ab) is therefore an attractive strategy to induce or boost tumour immune responses.
NYESO1 and WT1 are well characterised, highly immunogenic TAA expressed by a broad array of tumour types. We developed recombinant human chimaeric IgG4 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 CD8+ cytotoxic T cells. Likewise, a HLA-A2-restricted NYESO1 epitope was cross-presented Ag specific CD8+ T cells 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. Moreover, using a humanised mouse model in which functional human CD141+ DC and Ag-specific T cells develop, CLEC9A-TAA Ab induced priming of Ag-specific T cells.
Our data advocate further development of human CLEC9A targeting Abs as cancer vaccines.
Mater Research Institute.
Department of Defense, USA.
All authors have declared no conflicts of interest.