A SARS-CoV-2 spike-derived adjuvant peptide boosts IL-17/IFN-γ immunity and improves anti-PD-L1 therapy against
Chia-Hung Chen1,2, Tzu-Han Weng3, Ta-Wei Kuo4
1Department of Medical Research, Hsinchu MacKay Memorial Hospital, Hsinchu City, 30071, Taiwan, ROC.
Background:
PD-L1 immunotherapy plays a crucial role in cancer treatment, but PD-L1 peptide vaccines have low immunogenicity. A potent peptide derived from the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a significant adjuvant effect, which may increase the immunogenicity of the PD-L1 peptide. This study evaluates whether the PD-L1-SARS peptide enhances PD-L1 immunotherapy and analyzes its potential synergistic effects with anti-PD-L1 antibodies.
Methods:
In vivo experiments compared prevention, therapy, and combination therapy using PD-L1 versus PD-L1-SARS peptides in mice. Cytokine multiplex arrays, ELISpot, and IHC were used to evaluate adjuvant effects. Molecular docking (hypothesis-generating), RNA-seq, and LC-MS/MS were used to explore putative mechanisms.
Results:
The PD-L1-SARS peptide enhanced the Th1 immune response and increased CD8 and Th17 cell infiltration, effectively inhibiting tumor growth and liver metastasis. Additionally, it promoted M1 macrophage polarization and improved anti-PD-L1 antibody efficacy. Proteomics and bioinformatic analyses were consistent with IFN-γ-linked pathways, and an exploratory docking screen nominated candidate receptors/pathways potentially connecting the adjuvant motif to innate sensing.
Conclusions:
Embedding a SARS-derived adjuvant-like motif within a PD-L1 peptide vaccine and delivering it in situ may re-condition the tumor microenvironment toward an immune-activating, Th1/Th17-biased state and complement PD-L1 blockade.
Insights
A novel PD-L1 peptide vaccine incorporating a SARS-CoV-2 adjuvant motif enhances anti-PD-L1 immunotherapy by boosting immune cell activity and improving tumor inhibition. This combination therapy shows promise for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Vaccine Development
Background:
- Programmed death-ligand 1 (PD-L1) immunotherapy is vital in cancer treatment, but PD-L1 peptide vaccines exhibit limited immunogenicity.
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-derived peptides possess potent adjuvant properties that may enhance PD-L1 peptide immunogenicity.
Purpose of the Study:
- To assess if a PD-L1 peptide vaccine combined with a SARS-CoV-2 adjuvant motif (PD-L1-SARS) improves PD-L1 immunotherapy efficacy.
- To investigate the synergistic effects of the PD-L1-SARS peptide vaccine and anti-PD-L1 antibodies.
Main Methods:
- In vivo mouse models were used to compare PD-L1 and PD-L1-SARS peptides in prevention, therapy, and combination therapy settings.
- Immune responses were evaluated using cytokine multiplex arrays, ELISpot, and immunohistochemistry (IHC).
- Mechanisms were explored via molecular docking, RNA-sequencing (RNA-seq), and liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Main Results:
- The PD-L1-SARS peptide significantly boosted Th1 immune responses and increased CD8 and Th17 cell infiltration, leading to reduced tumor growth and liver metastasis.
- This peptide promoted M1 macrophage polarization and enhanced the effectiveness of anti-PD-L1 antibody therapy.
- Proteomic and bioinformatic analyses indicated involvement of IFN-γ-linked pathways, with docking suggesting potential innate sensing mechanisms.
Conclusions:
- Integrating a SARS-derived adjuvant motif into a PD-L1 peptide vaccine and administering it in situ can shift the tumor microenvironment towards an immune-activating, Th1/Th17-biased state.
- This approach complements PD-L1 blockade therapy, offering a potential strategy to overcome immunotherapy resistance.
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