Glycans as Immune Checkpoints: Removal of Branched N-glycans Enhances Immune Recognition Preventing Cancer Progression

TLDR

Tumor growth is accompanied by aberrant expression of complex branched N‑glycans, whose role in immune evasion and the effect of their removal on immune recognition remain unclear. The study aimed to determine whether removing these protumoral N‑glycans enhances immune recognition and unleashes an antitumor immune response. We found that colorectal cancer cells use branched N‑glycans to evade detection by suppressing IFNγ, but deglycosylation exposes immunogenic mannose residues that activate DC‑SIGN‑expressing cells, establishing a glycoimmune checkpoint whose removal triggers a potent antitumor response and improves immunotherapy efficacy.

Abstract

Tumor growth is accompanied with dramatic changes in the cellular glycome, such as the aberrant expression of complex branched N-glycans. However, the role of this protumoral N-glycan in immune evasion and whether its removal contributes to enhancement of immune recognition and to unleashing an antitumor immune response remain elusive. We demonstrated that branched N-glycans are used by colorectal cancer cells to escape immune recognition, instructing the creation of immunosuppressive networks through inhibition of IFNγ. The removal of this "glycan-mask" exposed immunogenic mannose glycans that potentiated immune recognition by DC-SIGN-expressing immune cells, resulting in an effective antitumor immune response. We revealed a glycoimmune checkpoint in colorectal cancer, highlighting the therapeutic efficacy of its deglycosylation to potentiate immune recognition and, thus, improving cancer immunotherapy.