Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune
Yuki Mizumoto1, Hiroaki Hemmi2, Masahiro Katsuda1
1Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
Background:
Cancer peptide vaccines show only marginal effects against cancers. Immune checkpoint inhibitors (ICIs) show significant curative effects in certain types of cancers, but the response rate is still limited. In this study, we aim to improve cancer peptide vaccination by targeting Ag peptides selectively to a dendritic cell (DC) subset, XCR1-expressing DCs (XCR1+ DCs), with high ability to support CD8+ T-cell responses.
Methods:
We have generated a fusion protein, consisting of an Ag peptide presented with MHC class I, and an XCR1 ligand, XCL1, and examined its effects on antitumour immunity in mice.
Results:
The fusion protein was delivered to XCR1+ DCs in an XCR1-dependent manner. Immunisation with the fusion protein plus an immune adjuvant, polyinosinic:polycytidylic acids (poly(I:C)), more potently induced Ag-specific CD8+ T-cell responses through XCR1 than the Ag peptide plus poly(I:C) or the Ag protein plus poly(I:C). The fusion protein plus poly(I:C) inhibited the tumour growth efficiently in the prophylactic and therapeutic tumour models. Furthermore, the fusion protein plus poly(I:C) showed suppressive effects on tumour growth in synergy with anti-PD-1 Ab.
Conclusions:
Cancer Ag targeting to XCR1+ DCs should be a promising procedure as a combination anticancer therapy with immune checkpoint blockade.
Insights
Targeting cancer antigens to XCR1-expressing dendritic cells (DCs) via a novel fusion protein enhances CD8+ T-cell responses. This approach shows potent anti-tumor effects and synergizes with immune checkpoint inhibitors for improved cancer therapy.
Area of Science:
- Immunology
- Oncology
- Vaccine Development
Background:
- Cancer peptide vaccines offer limited efficacy.
- Immune checkpoint inhibitors (ICIs) have shown success but have limited response rates.
- Targeting specific dendritic cell (DC) subsets may improve cancer vaccination.
Purpose of the Study:
- To improve cancer peptide vaccination by targeting antigens to XCR1-expressing DCs (XCR1+ DCs).
- To enhance CD8+ T-cell responses for anti-tumor immunity.
Main Methods:
- Generated a fusion protein linking an antigen peptide (MHC class I) with an XCR1 ligand (XCL1).
- Administered the fusion protein to mice to assess its effects on anti-tumor immunity.
- Evaluated the fusion protein's efficacy alone and in combination with polyinosinic:polycytidylic acids (poly(I:C)) and anti-PD-1 antibody.
Main Results:
- Fusion protein delivery to XCR1+ DCs was XCR1-dependent.
- Fusion protein plus poly(I:C) induced potent Ag-specific CD8+ T-cell responses, surpassing controls.
- This combination demonstrated efficient tumor growth inhibition in prophylactic and therapeutic models.
- Synergistic tumor suppression was observed with anti-PD-1 antibody.
Conclusions:
- Targeting cancer antigens to XCR1+ DCs is a promising strategy.
- This approach holds potential as a combination therapy with immune checkpoint blockade for cancer treatment.
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