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Immunogenicity of mRNA encoded MUC1 glycopeptides toward CAR-T cells
Yu He1, Bingchen Zhou2, Jiao Tong1
1Department of Immunology and Pathogen Biology, Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Tongji University School of Medicine, Shanghai 200092, China.
Abstract:
Vaccines and antibodies targeting hypoglycosylated glycoproteins have been focus of cancer immunotherapy. mRNA vaccines have shown success in inducing effective T cell immunity and antibody responses to viral glycoproteins and tumor antigens. However, the immunogenicity of mRNA-encoded cancer glycoproteins such as MUC1 remains unknown. In this study, we employed chimeric antigen receptor T cells as a caliber to measure the signaling strength of MUC1 glycopeptides encoded by mRNA vaccines. The results showed that glycopeptide within a single tandem repeat showed higher stimulation than glycopeptide bearing multiple tandem repeat sequence. Furthermore, more than five-fold higher stimulation was achieved when MUC1 glycopeptide was fused to GPI-anchor. Molecular mobility of glycopeptide antigens was measured by total internal reflection fluorescence microscopy, and glycosylphosphatidylinositol (GPI)-anchored MUC1 antigens showed faster diffusion than MUC1 glycopeptide with its own transmembrane domain. Our study reveals complex mechanisms by which the glycoproteins interacts with CAR-T cells. The combined used of mRNA vaccines targeting CAR-T cells with those targeting B cells, may be further studied to synergize the cellular and humoral arms of immunity.
Insights
Messenger RNA (mRNA) vaccines encoding cancer glycoproteins like MUC1 show potential for immunotherapy. This study found MUC1 glycopeptides with a glycosylphosphatidylinositol (GPI)-anchor enhance chimeric antigen receptor T-cell stimulation.
Area of Science:
- Immunology
- Biochemistry
- Molecular Biology
Background:
- Cancer immunotherapy research focuses on targeting cancer glycoproteins.
- Messenger RNA (mRNA) vaccines are effective for T-cell and antibody responses against viral glycoproteins and tumor antigens.
- The immunogenicity of mRNA-encoded cancer glycoproteins, such as MUC1, requires further investigation.
Purpose of the Study:
- To assess the immunogenicity of mRNA-encoded MUC1 glycopeptides.
- To evaluate the signaling strength of MUC1 glycopeptides using chimeric antigen receptor T cells (CAR-T).
- To investigate the impact of MUC1 glycopeptide structure and anchoring on T-cell activation.
Main Methods:
- Utilized CAR-T cells to measure signaling strength of MUC1 glycopeptides encoded by mRNA vaccines.
- Compared stimulation levels of single versus multiple tandem repeat MUC1 glycopeptides.
- Assessed the effect of glycosylphosphatidylinositol (GPI)-anchoring on MUC1 glycopeptide stimulation.
- Employed total internal reflection fluorescence microscopy to measure molecular mobility of MUC1 glycopeptide antigens.
Main Results:
- MUC1 glycopeptides within a single tandem repeat demonstrated higher T-cell stimulation compared to those with multiple tandem repeats.
- Fusion of MUC1 glycopeptide to a GPI-anchor resulted in over five-fold higher stimulation.
- GPI-anchored MUC1 antigens exhibited faster molecular diffusion than MUC1 glycopeptides with their own transmembrane domain.
Conclusions:
- MUC1 glycopeptide structure and anchoring significantly influence CAR-T cell interactions and signaling.
- GPI-anchoring enhances MUC1 antigen presentation and T-cell activation.
- Future research could explore combining mRNA vaccines targeting CAR-T cells and B cells to synergize cellular and humoral immunity for cancer immunotherapy.
