Total serum N-glycans associate with response to immune checkpoint inhibition therapy and survival in patients with advanced melanoma

Visconti, Alessia; Rossi, Niccolò; Deriš, Helena; Lee, Karla A.; Trbojević‐Akmačić, Irena; Thomas, Andrew Maltez; Bolte, Laura A; Björk, Johannes; Hooiveld-Noeken, Jahlisa S.; Board, Ruth; Harland, Mark; Newton-Bishop, Julia; Harries, Mark; Sacco, Joseph J.; Lorigan, Paul; Shaw, Heather; Vries, Elisabeth G.E. de; Fehrmann, Rudolf S.N.; Weersma, Rinse K.; Spector, Tim D.; Nathan, Paul; Hospers, Geke A.P.; Sasieni, Peter; Bataille, Véronique; Lauc, Gordan; Falchi, Mario

doi:10.1186/s12885-023-10511-3

Cited by 6 publications

(6 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also discovered a specific fucosylation signature in plasma N-glycoproteins of patients that do not achieve a durable response to ICI therapy. Interestingly, higher levels of N-glycans containing fucose have been recently reported in association with reduced PFS in a glycomics study investigating responses to ICI (52). Elevated protein fucosylation, potentially resulting from increased expression of fucosyltransferases, has been described in the tumor microenvironment (TME) in melanoma (53).…”

Section: Discussionmentioning

confidence: 99%

Plasma glycoproteomic biomarkers identify metastatic melanoma patients with reduced clinical benefit from immune checkpoint inhibitor therapy

Pickering

Aiyetan

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

The clinical success of immune-checkpoint inhibitors (ICI) in both resected and metastatic melanoma has confirmed the validity of therapeutic strategies that boost the immune system to counteract cancer. However, half of patients with metastatic disease treated with even the most aggressive regimen do not derive durable clinical benefit. Thus, there is a critical need for predictive biomarkers that can identify individuals who are unlikely to benefit with high accuracy so that these patients may be spared the toxicity of treatment without the likely benefit of response. Ideally, such an assay would have a fast turnaround time and minimal invasiveness. Here, we utilize a novel platform that combines mass spectrometry with an artificial intelligence-based data processing engine to interrogate the blood glycoproteome in melanoma patients before receiving ICI therapy. We identify 143 biomarkers that demonstrate a difference in expression between the patients who died within six months of starting ICI treatment and those who remained progression-free for three years. We then develop a glycoproteomic classifier that predicts benefit of immunotherapy (HR=2.7; p=0.026) and achieves a significant separation of patients in an independent cohort (HR=5.6; p=0.027). To understand how circulating glycoproteins may affect efficacy of treatment, we analyze the differences in glycosylation structure and discover a fucosylation signature in patients with shorter overall survival (OS). We then develop a fucosylation-based model that effectively stratifies patients (HR=3.5; p=0.0066). Together, our data demonstrate the utility of plasma glycoproteomics for biomarker discovery and prediction of ICI benefit in patients with metastatic melanoma and suggest that protein fucosylation may be a determinant of anti-tumor immunity.

show abstract

Section: Discussionmentioning

confidence: 99%

Plasma glycoproteomic biomarkers identify metastatic melanoma patients with reduced clinical benefit from immune checkpoint inhibitor therapy

Pickering

Aiyetan

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Altogether, our studies suggest that the negative impact of Fuc on patient outcome could be mediated by its potent hijacking of DC function. Strikingly, by investigating the N‐glycome of total serum proteins in melanoma patients treated with ICB with the goal to identify glyco‐markers of response to the therapy, Visconti et al observed that responders to ICB displayed a pre‐treatment N‐glycome profile significantly shifted towards higher abundancy of low‐branched structures containing lower abundances of antennary Fuc [60]. In addition, this profile was positively associated with survival and a better predictor of response than clinical variables alone.…”

Section: Discussionmentioning

confidence: 99%

Melanoma tumour‐derived glycans hijack dendritic cell subsets through C‐type lectin receptor binding

Niveau,

Sosa Cuevas,

Roubinet

et al. 2023

Immunology

View full text Add to dashboard Cite

Dendritic cell (DC) subsets play a crucial role in shaping anti‐tumour immunity. Cancer escapes from the control immune system by hijacking DC functions. Yet, bases for such subversion are only partially understood. Tumour cells display aberrant glycan motifs on surface glycoproteins and glycolipids. Such carbohydrate patterns can be sensed by DCs through C‐type lectin receptors (CLRs) that are critical to shape and orientate immune responses. We recently demonstrated that melanoma tumour cells harboured an aberrant ‘glyco‐code,’ and that circulating and tumour‐infiltrating DCs from melanoma patients displayed major perturbations in their CLR profiles. To decipher whether melanoma, through aberrant glycan patterns, may exploit CLR pathways to mislead DCs and evade immune control, we explored the impact of glycan motifs aberrantly found in melanoma (neoglycoproteins [NeoGP] functionalised with Gal, Man, GalNAc, s‐Tn, fucose [Fuc] and GlcNAc residues) on features of human DC subsets (cDC2s, cDC1s and pDCs). We examined the ability of glycans to bind to purified DCs, and assessed their impact on DC basal properties and functional features using flow cytometry, confocal microscopy and multiplex secreted protein analysis. DC subsets differentially bound and internalised NeoGP depending on the nature of the glycan. Strikingly, Fuc directly remodelled the expression of activation markers and immune checkpoints, as well as the cytokine/chemokine secretion profile of DC subsets. NeoGP interfered with Toll like receptor (TLR)‐signalling and pre‐conditioned DCs to exhibit an altered response to subsequent TLR stimulation, dampening antitumor mediators while triggering pro‐tumoral factors. We further demonstrated that DC subsets can bind NeoGP through CLRs, and identified GalNAc/MGL and s‐Tn/ C‐type lectin‐like receptor 2 (CLEC2) as potential candidates. Moreover, DC dysfunction induced by tumour‐associated carbohydrate molecules may be reversed by interfering with the glycan/CLR axis. These findings revealed the glycan/CLR axis as a promising checkpoint to exploit in order to reshape potent antitumor immunity while impeding immunosuppressive pathways triggered by aberrant tumour glycosylation patterns. This may rescue DCs from tumour hijacking and improve clinical success in cancer patients.

show abstract

“…While currently underexplored, glycoprofiling of new or validated drug targets represents a valuable opportunity for development of next generation therapeutics that may achieve exquisite selectivity by binding to distinct glycosylation variants. Additionally, the recent discovery of fucosylated biomarkers in blood of melanoma patients that failed to achieve extended survival following treatment with immune checkpoint inhibitors point to a role of glycosylation not only in the tumor but also in the periphery 24,25 . Therefore, glycosylation analysis of circulating glycoproteins may offer crucial information for both drug design and biomarker discovery.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we observed that camrelizumab and cemiplimab specifically interact with a fucose moiety within the N58 glycan of PD-1. As fucosylation is increased in cancer and fucosylated biomarkers in blood have been associated with a lack of benefit of immune checkpoint inhibitor therapy 24,25 , we investigated the influence of fucosylation on PD-1 in antibody activity by a combination of protein-and cell-based assays. Furthermore, we characterized fucosylation of sPD-1 in serum of individuals with non-small cell lung cancer (NSCLC).…”

Section: Introductionmentioning

confidence: 99%

Variable PD-1 glycosylation modulates the activity of immune checkpoint inhibitors

Chu,

Čaval,

Alisson-Silva

et al. 2023

Preprint

View full text Add to dashboard Cite

Monoclonal antibodies targeting the immune checkpoint PD-1 have provided significant clinical benefit across a number of solid tumors, with differences in efficacy and toxicity profiles possibly related to their intrinsic molecular properties. Here, we report that camrelizumab and cemiplimab engage PD-1 through interactions with its fucosylated glycan. Using a combination of protein and cell glycoengineering, we demonstrate that the two antibodies bind preferentially to PD-1 with a core fucose at the asparagine N58 residue. We then provide evidence that the concentration of fucosylated PD-1 in the blood of non-small cell lung cancer patients varies across different stages of disease. This study illustrates how glycoprofiling of surface receptors and related circulating forms can inform the development of differentiated antibodies that discriminate glycosylation variants and achieve enhanced selectivity and paves the way towards the implementation of personalized therapeutic approaches.

show abstract

Total serum N-glycans associate with response to immune checkpoint inhibition therapy and survival in patients with advanced melanoma

Cited by 6 publications

References 46 publications

Plasma glycoproteomic biomarkers identify metastatic melanoma patients with reduced clinical benefit from immune checkpoint inhibitor therapy

Plasma glycoproteomic biomarkers identify metastatic melanoma patients with reduced clinical benefit from immune checkpoint inhibitor therapy

Melanoma tumour‐derived glycans hijack dendritic cell subsets through C‐type lectin receptor binding

Variable PD-1 glycosylation modulates the activity of immune checkpoint inhibitors

Contact Info

Product

Resources

About