Figure 3.

Fucosylation signatures in peripheral blood N-glycoproteins are associated with reduced clinical benefit of ICI therapy. (A) Differentially expressed glycopeptides (p<0.05), based on relative abundance measurements, in patients who are likely to benefit compared to those unlikely to benefit were classified based on their glycan structure. N-linked glycopeptides are separated into two groups based on the presence or absence of fucose; fucosylation is strongly associated with OS (p<0.0001). The number of sialic acid residues, however, is not associated with OS. HR, hazard ratio. (B) Di-sialylated O-glycopeptides are enriched in samples with reduced OS (p=0.14). (C) Effect of site occupancy on protein function in relation to likelihood to benefit. Lack of a glycan on site N70 of alpha-1-antitrypsin (A1AT_N70 NG) is associated with increased OS, whereas absence of glycosylation at the site N1424 of alpha-2-macroglobulin is associated with reduced OS. The four-digit number describes glycan composition (number of hexoses, N-acetyl-hexosamines, fucoses, and sialic acids, respectively). (D) Hazard ratios of 51 fucose-dependent monomer weight features derived from N-glycopeptides, sorted by age- and sex-adjusted Cox regression FDR. Hazard ratios of features that achieved FDR<0.05 are represented as filled-in diamonds. HR>1 represents association with shorter OS. (E) Kaplan-Meier curves showing performance of repeated five-fold cross-validated LASSO-regularized Cox regression-based classifier using 11 fucose-dependent features derived from N-glycopeptides that achieved FDR<0.05 in age- and sex-adjusted Cox regression analysis.