Defective N‐glycosylation in tumor‐infiltrating CD8⁺ T cells impairs IFN‐γ‐mediated effector function

Abstract

T cell-mediated antitumor immunity is modulated, in part, by N-glycosylation. However, the interplay between N-glycosylation and the loss of effector function in exhausted T cells has not yet been fully investigated. Here, we delineated the impact of N-glycosylation on the exhaustion of tumorinfiltrating lymphocytes in a murine colon adenocarcinoma model, focusing on the IFN-γ-mediated immune response. We found that exhausted CD8 + T cells downregulated the oligosaccharyltransferase complex, which is indispensable for N-glycan transfer. Concordant N-glycosylation deficiency in tumor-infiltrating lymphocytes leads to loss of antitumor immunity. Complementing the oligosaccharyltransferase complex restored IFN-γ production and alleviated CD8 + T cell exhaustion, resulting in reduced tumor growth. Thus, aberrant glycosylation induced in the tumor microenvironment incapacitates effector CD8 + T cells. Our findings provide insights into CD8 + T cell exhaustion by incorporating N-glycosylation to understand the characteristic loss of IFN-γ, opening new opportunities to amend the glycosylation status in cancer immunotherapies.

Tumor glucose metabolism and the T cell glycocalyx: implication for T cell function

“…Restoration of N-linked glycosylation enhanced mitochondrial respiration again in CD4 + T cells exposed to malignant ovarian ascites (110). In addition to CD4 + T cells, Kim et al (111) demonstrated that deficient N-glycosylation impairs IFNg mediated effector function also in tumor-infiltrating CD8 + T cells, impacting the anti-tumor immune response. Mechanistically, tumor infiltrating and exhausted CD8 + T cells downregulate the oligosaccharyltransferase (OST) complex.…”

“…OST complex is therefore indispensable for the N-glycosylation pathway. Interestingly, restoration of the OST complex complemented Nglycosylation that restored the IFNg production and alleviated CD8 + T cell exhaustion, consequently resulting in reduced tumor growth in preclinical models (111).…”