Recombinant fusion proteins for targeting dendritic cell subsets in therapeutic cancer vaccine
Stéphanie Corgnac1, Natalia K Botelho2, Alena Donda2
1Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland; INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, PSL, Fac. de Médecine-Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France.
Abstract:
Dendritic cells (DCs) are professional antigen-presenting cells, which are optimal for the priming of a T cell response against pathogens and tumors. Therefore, many efforts are made to develop therapeutic cancer vaccines which preferentially target the antigen to DC subsets. To this aim, we developed two types of recombinant fusion proteins, which favor antigen delivery to pro-inflammatory DCs as well as the crosstalk between specialized subpopulations of DCs. The first approach combines peptide/CpG vaccination with the recruitment of iNKT cells to the tumor site via CD1d-antitumor scFv fusion proteins. The second approach is targeting the tumor antigen to cross-presenting Xcr1+ DCs via a fusion protein made of Xcl1 fused to a synthetic long peptide followed by an IgG1 Fc fragment. Both strategies allow a potent tumor-specific CD8 T cell response associated with tumor regression or tumor growth delay depending on the model. In the case of iNKT cell activation, the strategy relies on a strong IL-12 release by splenic DCs, while in the second case, the T cell response is strictly dependent on the presence of Xcr1+ cross-presenting DCs.
Insights
Two novel fusion proteins enhance cancer vaccines by targeting dendritic cells (DCs), promoting T cell responses and tumor regression. These strategies leverage specific DC subsets for potent anti-tumor immunity.
Area of Science:
- Immunology
- Cancer Research
- Vaccine Development
Background:
- Dendritic cells (DCs) are crucial for initiating T cell responses against tumors.
- Targeting antigens to specific DC subsets can optimize cancer vaccine efficacy.
- Developing strategies to enhance DC-mediated antigen presentation is a key goal in cancer immunotherapy.
Purpose of the Study:
- To develop novel recombinant fusion proteins for targeted antigen delivery to dendritic cells (DCs).
- To enhance anti-tumor T cell responses by promoting DC subset crosstalk and activation.
- To evaluate the efficacy of these strategies in promoting tumor regression or growth delay.
Main Methods:
- Development of two distinct fusion protein strategies for antigen targeting.
- Strategy 1: Combining peptide/CpG vaccination with iNKT cell recruitment via CD1d-antitumor scFv fusion proteins.
- Strategy 2: Targeting Xcr1+ DCs using an Xcl1-based fusion protein linked to a synthetic long peptide and IgG1 Fc fragment.
Main Results:
- Both fusion protein strategies induced potent tumor-specific CD8 T cell responses.
- Strategy 1 activated iNKT cells, leading to IL-12 release by splenic DCs.
- Strategy 2 demonstrated a T cell response strictly dependent on Xcr1+ cross-presenting DCs, resulting in tumor regression or growth delay.
Conclusions:
- Recombinant fusion proteins can effectively target DCs for enhanced anti-tumor immunity.
- Targeting specific DC subsets (iNKT cells or Xcr1+ DCs) offers distinct pathways for potent T cell activation.
- These strategies hold promise for the development of effective therapeutic cancer vaccines.
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