Whole-cell tumor vaccines desialylated to uncover tumor antigenic Gal/GalNAc epitopes elicit anti-tumor immunity

Background: Aberrant sialoglycans on the surface of tumor cells shield potential tumor antigen epitopes, escape recognition, and suppress activation of immunocytes. alpha 2,3/alpha 2,6Gal- and alpha 2,6GalNAc (Gal/GalNAc)-linked sialic acid residues of sialoglycans could affect macrophage galactose-type lectins (MGL) mediated-antigen uptake and presentation and promote sialic acid-binding immunoglobulin-like lectins (Siglecs) mediated-immunosuppression. Desialylating sialoglycans on tumor cells could present tumor antigens with Gal/GalNAc residues and overcome glycoimmune checkpoints. Thus, we explored whether vaccination with desialylated whole-cell tumor vaccines (DWCTVs) triggers anti-tumor immunity in ovarian cancer (OC). Methods: Sialic acid (Sia) and Gal/GalNAc residues on OC A2780, OVCAR3, and ID8 cells treated with alpha 2-3 neuraminidase (alpha 2-3NA) and alpha 2-6NA, and Sigec-9 or Siglec-E and MGL on DCs pulsed with desialylated OC cells were identified using flow cytometry (FCM); RT-qPCR determined IFNG expression of T cells, TRBV was sequenced using Sanger sequencing and cytotoxicity of alpha beta T cells was measured with LDH assay; Anti-tumor immunity in vivo was validated via vaccination with desialylated whole-cell ID8 vaccine (ID8 DWCTVs). Results: Gal/GalNAc but not Sia residues were significantly increased in the desialylated OC cells. alpha 2-3NA-modified DWCTV increased MGL but decreased Siglec-9 or Siglec E expression on DCs. MGL(bright)/Siglec-9(dim) DCs significantly up-regulated IFNG expression and CD4/CD8 ratio of T cells and diversified the TCR repertoire of aPT-cells that showed enhanced cytotoxic activity. Vaccination with alpha 2-3NA-modified ID8 DWCTVs increased MGL(bright)/Siglec-(EDCs)-D-dim in draining lymph nodes, limited tumor growth, and extended survival in tumor-challenged mice. Conclusion: Desialylated tumor cell vaccine could promote anti-tumor immunity and provide a strategy for OC immunotherapy in a clinical setting.

Automated summary

The study suggests that desialylated tumor cell vaccines can enhance tumor antigen presentation and overcome immune suppression, thereby promoting anti-tumor immunity. This research provides a new strategy for immunotherapy in ovarian cancer.