Targeting DNGR-1 (CLEC9A) with antibody/MUC1 peptide conjugates as a vaccine for carcinomas
Gianfranco Picco1, Richard Beatson, Joyce Taylor-Papadimitriou
1Breast Cancer Biology, King's College London, Guy's Hospital, London, UK.
Abstract:
DCs are the most potent APCs and are the focus of many immunotherapeutic approaches for the treatment of cancer, although most of these approaches require the ex vivo generation and pulsing of DCs. We have targeted a subset of DCs in vivo using an Ab to DNGR-1, a C-type lectin dedicated to the cross-presentation of Ag expressed by subsets of DCs. HLA-A2 epitopes from the tumour-associated Ag, MUC1, were coupled to the anti-DNGR-1 Ab, and their efficacy in generating a Th1-cell response and inhibiting tumour growth was evaluated in a clinically relevant double transgenic mouse model expressing human MUC1 and A2K/b. Using this strategy, we demonstrate that an effective immune response to MUC1 can be generated, which results in a significant delay in the growth of MUC1-expressing tumours in both prophylactic and therapeutic settings. In addition, we also show, using PBMCs isolated from healthy volunteer blood, that target an MUC1 HLA-A2 epitope to human DNGR-1 in vitro can induce an MUC1-specific CD8(+) -T-cell response, which confirms the relevance of our in vivo murine results in the human setting.
Insights
Targeting dendritic cells (DCs) in vivo with anti-DNGR-1 antibodies linked to MUC1 epitopes effectively generates anti-tumor immunity. This approach delays MUC1-expressing tumor growth in mice and induces MUC1-specific CD8+ T-cell responses in humans.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- Dendritic cells (DCs) are potent antigen-presenting cells (APCs) crucial for cancer immunotherapy.
- Current DC-based cancer immunotherapies often necessitate ex vivo manipulation.
- Targeting DCs in vivo offers a promising alternative for therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy of in vivo targeting of a DC subset via DNGR-1 for cancer immunotherapy.
- To assess the potential of MUC1 epitopes coupled to anti-DNGR-1 antibodies in generating anti-tumor immune responses.
- To validate the translational relevance of this approach in both murine models and human settings.
Main Methods:
- Utilized an antibody targeting DNGR-1, a C-type lectin specific for DC cross-presentation.
- Coupled HLA-A2 epitopes from the tumor-associated antigen MUC1 to the anti-DNGR-1 antibody.
- Evaluated immune response and tumor growth inhibition in a double transgenic mouse model (hMUC1, hA2K/b) and human PBMCs.
Main Results:
- Demonstrated the generation of a robust Th1-cell response against MUC1.
- Observed a significant delay in MUC1-expressing tumor growth in both prophylactic and therapeutic settings.
- Confirmed the induction of MUC1-specific CD8+ T-cell responses in human PBMCs targeting DNGR-1.
Conclusions:
- In vivo targeting of DNGR-1 with MUC1 epitopes represents a viable strategy for cancer immunotherapy.
- This approach elicits effective anti-tumor immunity, delaying tumor progression.
- The findings highlight the translational potential of this method for human cancer treatment.
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