title: ImmTAC-redirected tumour cell killing induces and potentiates antigen cross-presentation by dendritic cells.
abstract: Antigen cross-presentation by dendritic cells (DCs) is thought to play a critical role in driving a polyclonal and durable T cell response against cancer. It follows, therefore, that the capacity of emerging immunotherapeutic agents to orchestrate tumour eradication may depend on their ability to induce antigen cross-presentation. ImmTACs [immune-mobilising monoclonal TCRs (T cell receptors) against cancer] are a new class of soluble bi-specific anti-cancer agents that combine pico-molar affinity TCR-based antigen recognition with T cell activation via a CD3-specific antibody fragment. ImmTACs specifically recognise human leucocyte antigen (HLA)-restricted tumour-associated antigens, presented by cancer cells, leading to T cell redirection and a potent anti-tumour response. Using an ImmTAC specific for a HLA-A*02-restricted peptide derived from the melanoma antigen gp100 (termed IMCgp100), we here observe that ImmTAC-driven melanoma-cell death leads to cross-presentation of melanoma antigens by DCs. These, in turn, can activate both melanoma-specific T cells and polyclonal T cells redirected by IMCgp100. Moreover, activation of melanoma-specific T cells by cross-presenting DCs is enhanced in the presence of IMCgp100; a feature that serves to increase the prospect of breaking tolerance in the tumour microenvironment. The mechanism of DC cross-presentation occurs via 'cross-dressing' which involves the rapid and direct capture by DCs of membrane fragments from dying tumour cells. DC cross-presentation of gp100-peptide-HLA complexes was visualised and quantified using a fluorescently labelled soluble TCR. These data demonstrate how ImmTACs engage with the innate and adaptive components of the immune system enhancing the prospect of mediating an effective and durable anti-tumour response in patients.
authors: Immunocore Ltd, 57 Jubilee Avenue Milton Park, Abingdon, Oxon, OX14 4RX, UK.
authors: Giovanna
authors: G
authors: Bossi
authors: Sandrine
authors: S
authors: Buisson
authors: Joanne
authors: J
authors: Oates
authors: Bent K
authors: BK
authors: Jakobsen
authors: Namir J
authors: NJ
authors: Hassan
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008545:Melanoma / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology*; D058951:gp100 Melanoma Antigen / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D011948:Receptors, Antigen, T-Cell; D058951:gp100 Melanoma Antigen