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

• Published in: Immunology and cell biology 2023-08, Vol.101 (7), p.610-624
• Main Authors: Kim, Soyeon, Min, Hyungyu, Nah, Jinwoo, Jeong, Jinguk, Park, Kyungsoo, Kim, Wooseob, Lee, Youngjin, Kim, Jieun, An, Jungeun, Seong, Rho Hyun
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Cancer immunotherapy; CD8 antigen; Effector cells; Glycosylation; IFN‐γ; Immunity; Lymphocytes T; N‐glycosylation; Oligosaccharyltransferase; T cell exhaustion; tumor immunology; Tumor microenvironment; Tumors; tumor‐infiltrating lymphocytes
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1111/imcb.12647

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 tumor‐infiltrating 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. In this study, we investigated how defective N‐glycosylation contributes to the exhaustion of tumor‐infiltrating CD8+ T cells by impairing IFN‐γ‐mediated effector function. Downregulation of the oligosaccharyltransferase (OST) complex and the concordant loss of fully‐N‐glycosylated IFN‐γ were observed in exhausted CD8+ T cells. We further report that complementing the OST complex augmented IFN‐γ production and enhanced antitumor immunity.