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Fucosylation of HLA-DRB1 regulates CD4+T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy: CD4+ T Cell Phosphoproteomics

ABSTRACT: Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs)—thus, effective strategies to safely increase itICs are needed. We report that dietary administration of L-fucose induces fucosylation and cell surface enrichment of the MHC-II protein HLA-DRB1 in melanoma cells, triggering CD4+T cell-mediated increases in ItICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance and anti-PD1 responder status in patient melanoma specimens, suggesting the potential use of melanoma fucosylation as a strategy for stratifying patients for immunotherapies. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity, and importantly, suggest that L-fucose is a powerful agent for safely increasing ItICs and immunotherapy efficacy in melanoma.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell

DISEASE(S): Melanoma

SUBMITTER: John Koomen

LAB HEAD: Eric Lau, PhD

PROVIDER: PXD038065 | Pride | 2022-12-16

REPOSITORIES: Pride

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			Action	DRS
	Activate_DMSO_rep1.raw	Raw
	Activate_DMSO_rep1.raw__F003542_.dta	Raw
	Activate_DMSO_rep1.raw__F003542_.mzid.gz	Mzid
	Activate_DMSO_rep1.raw__F003542_.mzid_Activate_DMSO_rep1.raw__F003542_.MGF	Mzid
	Activate_DMSO_rep2.raw	Raw

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Fucosylation of HLA-DRB1 regulates CD4+T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy: HLA-DRB1 Interactomes

Project description:Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs)—thus, effective strategies to safely increase itICs are needed. We report that dietary administration of L-fucose induces fucosylation and cell surface enrichment of the MHC-II protein HLA-DRB1 in melanoma cells, triggering CD4+T cell-mediated increases in ItICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance and anti-PD1 responder status in patient melanoma specimens, suggesting the potential use of melanoma fucosylation as a strategy for stratifying patients for immunotherapies. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity, and importantly, suggest that L-fucose is a powerful agent for safely increasing ItICs and immunotherapy efficacy in melanoma.

2022-12-16 | PXD038068 | Pride

Fucosylation of HLA-DRB1 regulates CD4+T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy: Fucoproteomic profiling of CD4 T cells

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Fucosylation of HLA-DRB1 regulates CD4+T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy: Fucose Click Chemistry

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Gene expression profiling of fucose-deficient Fx-/- mice cDC1-enriched splenocytes

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Gene expression profiling of FUT8 knockdown CL1-5 cells

Project description:Overexpression of fucosyltransferase 8 (FUT8) is found in many cancers including liver, ovarian, thyroid, colorectal and non-small cell lung cancers. Unlike other FUTs which are functionally redundant, FUT8 is the only enzyme responsible for the alpha1,6-linked fucosylation (core fucosylation) by adding fucose to the innermost GlcNAc residue of an N-linked glycan. A growing body of evidence indicates that core fucosylation is important for regulating protein functions, such as EGFR, TGF beta receptor and integrins. To understand the downstream molecular events in response to the global alteration of core fucosylation during cancer progression, microarray analysis was employed to profile the changes in gene expression following FUT8 silencing. The genes significantly (2-fold, P<0.01) changed in CL1-5/shFUT8 cells were selected for functional annotations using a Gene Ontology database. The result revealed that many genes involved in cell adhesion, motility, growth, angiogenesis, and inflammation were under the control of core fucosylation.

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The Functional Role of L-fucose on Dendritic Cell Function and Polarization

Project description:Despite significant advances in the development and refinement of immunotherapies administered to combat cancer over the past decades, a number of barriers continue to limit their efficacy. One significant clinical barrier is the inability to mount initial immune responses towards the tumor. As dendritic cells are central initiators of immune responses in the body, the elucidation of mechanisms that can be therapeutically leveraged to enhance their functions to drive anti-tumor immune responses is urgently needed. Here, we report that the dietary sugar L-fucose can be used to enhance the immunostimulatory activity of dendritic cells (DCs). L-fucose polarizes immature myeloid cells towards specific DC subsets, specifically cDC1 and moDC subsets. In vitro, L-fucose treatment enhances antigen uptake and processing of DCs. Furthermore, our data suggests that L-fucose-treated DCs increase stimulation of T cell populations. Consistent with our functional assays, single-cell RNA sequencing of intratumoral DCs from breast tumor-bearing mice confirmed transcriptional regulation and antigen processing as pathways that are significantly altered by dietary L-fucose. Together, this study provides the first evidence of the ability of L-fucose to bolster DC functionality and provides rational to further investigate how L-fucose can be used to leverage DC function in order to enhance current immunotherapy.

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Gene expression profiling of FUT8 knockdown CL1-5 cells

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Aberrant L-Fucose accumulation and increased core fucosylation are specific metabolic liabilities in mesenchymal glioblastoma

Project description:Dysregulated metabolism in glioblastoma (GBM), the deadliest brain tumor of adults, offers an opportunity to deploy metabolic interventions as precise therapeutic strategies. To identify the molecular drivers and the modalities by which different molecular subgroups of GBM exploit metabolic rewiring to sustain tumor progression, we interrogated the transcriptome, the metabolome and the glycoproteome of human subgroup-specific GBM stem cells (GSCs). Here we report that L-Fucose abundance and core fucosylation activation are more highly enhanced in mesenchymal (MES) than in proneural (PN) GSCs; this pattern is retained in subgroup-specific xenografts and, most significantly, retrieved in subgroup-affiliated human patients’ samples. Genetic and pharmacological inhibition of core fucosylation in MES GBM preclinical models results in significant reduction in tumor burden. LC/MS-based glycoproteomic screening indicates that most MES-restricted core fucosylated proteins are involved in therapeutically relevant GBM pathological processes, such as extracellular matrix interaction, cell adhesion and integrin-mediated signaling. Notably, selective L-Fucose accumulation in MES GBMs is demonstrated by pre-clinical minimally-invasive positron emission tomography (PET), implying this metabolite as a potential subgroup-restricted biomarker. Overall, these findings indicate that L-Fucose pathway activation in MES GBM offers subgroup-specific, GSC-restricted dependencies to be exploited as diagnostic markers and actionable therapeutic targets.

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