Sialic acid removal from dendritic cells improves antigen cross-presentation and boosts anti-tumor immune responses

Silva, Mariana; Silva, Zélia; Marques, Graça; Ferro, Tiago; Gonçalves, Márcia; Monteiro, Mauro; Vliet, Sandra J. van; Mohr, Elodie; Lino, Andreia C.; Fernandes, Alexandra R.; Lima, Flávia Afonso; Kooyk, Yvette van; Matos, Teresa J.; Tadokoro, Carlos E.; Videira, Paula A.

doi:10.18632/oncotarget.9419

Cited by 39 publications

(44 citation statements)

References 40 publications

(48 reference statements)

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“…Several groups have reported that removal of surface sialic acids with bacterial sialidases enhanced the response of DCs to LPS. In addition to enhanced maturation and cytokine production upon LPS stimulation, DCs treated with sialidase were also more potent T‐cell activators 8 , 9 , 10 , 11 , 12 , 13 , 14 . These data evidence that sialic acids limit the response of DCs to stimulation via the TLR pathway.…”

Section: Introductionmentioning

confidence: 78%

Metabolic sialic acid blockade lowers the activation threshold of moDCs for TLR stimulation

et al. 2016

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Sialic acid sugars cover the surface of dendritic cells (DCs) and have been suggested to impact several aspects of DC biology. Research into the role of sialic acids in DCs, however, is complicated by the limited number of tools available to modulate sialic acid expression. Here we report on a synthetic, fluorinated sialic acid mimetic, Ac3FNeu5Ac, which potently blocks sialic acid expression in human monocyte-derived DCs (moDCs). Sialic acid blockade enhanced the responsiveness of moDCs to Toll-like receptor (TLR) stimulation as measured by increased maturation marker expression and cytokine production. Consequently, the T-cell activation capacity of Ac3FNeu5Ac-treated moDCs was strongly increased. In addition to sialic acids, moDCs also expressed the sialic acid-binding immunoglobulin-like lectins (Siglecs) -3, -5, -7, -9 and -10, immune inhibitory receptors recognizing these sialic acids. Treatment with Ac3FNeu5Ac abrogated putative cis and trans interactions between sialic acids and Siglec-7/-9. Together, these data indicate that sialic acids limit the activation of moDCs via the TLR pathway, potentially by interacting with Siglec-7 or Siglec-9. Metabolic sialic acid blockade with Ac3FNeu5Ac could therefore potentially be used to generate more potent DC-based vaccines for induction of robust anti-viral or anti-tumor immune responses.

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Section: Introductionmentioning

confidence: 78%

Metabolic sialic acid blockade lowers the activation threshold of moDCs for TLR stimulation

et al. 2016

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“…Desialylated DCs have higher expression of MHC-I, MHC-II and co-stimulatory molecules (e.g., CD80, CD86), and higher secretion of pro-inflammatory cytokines, which altogether contribute to a superior T H 1 anti-tumoral response. ST6Gal-I knockout DCs also show increased capacity to activate T cells, further supporting that the ability of DCs to induce T H 1 anti-tumoral responses is improved by sialic acid removal [16,17]. Initially thought as mere induction of DC maturation [16] the fact is that the molecular mechanisms behind this outcome are still poorly characterized.…”

Section: Introductionmentioning

confidence: 86%

“…The levels of sialic acid at DCs surface were shown to modulate the maturation status of both murine and human DCs [16]. Previous results from our group showed that the temporary removal of surface sialic acids by sialidase treatment increased the ability of human monocyte-derived DCs to activate T cells and to provide antigen-specific anti-tumoral responses [17]. Desialylated DCs have higher expression of MHC-I, MHC-II and co-stimulatory molecules (e.g., CD80, CD86), and higher secretion of pro-inflammatory cytokines, which altogether contribute to a superior T H 1 anti-tumoral response.…”

Section: Introductionmentioning

confidence: 96%

MHC Class I Stability is Modulated by Cell Surface Sialylation in Human Dendritic Cells

et al. 2020

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Maturation of human Dendritic Cells (DCs) is characterized by increased expression of antigen presentation molecules, and overall decreased levels of sialic acid at cell surface. Here, we aimed to identify sialylated proteins at DC surface and comprehend their role and modulation. Mass spectrometry analysis of DC’s proteins, pulled down by a sialic acid binding lectin, identified molecules of the major human histocompatibility complex class I (MHC-I), known as human leucocyte antigen (HLA). After desialylation, DCs showed significantly higher reactivity with antibodies specific for properly folded MHC-I-β2-microglobulin complex and for β2-microglobulin but showed significant lower reactivity with an antibody specific for free MHC-I heavy chain. Similar results for antibody reactivities were observed for TAP2-deficient lymphoblastoid T2 cells, which express HLA-A*02:01. Using fluorescent peptide specifically fitting the groove of HLA-A*02:01, instead of antibody staining, also showed higher peptide binding on desialylated cells, confirming higher surface expression of MHC-I complex. A decay assay showed that desialylation doubled the half-life of MHC-I molecules at cell surface in both DCs and T2 cells. The biological impact of DC´s desialylation was evaluated in co-cultures with autologous T cells, showing higher number and earlier immunological synapses, and consequent significantly increased production of IFN-γ by T cells. In summary, sialic acid content modulates the expression and stability of complex MHC-I, which may account for the improved DC-T synapses.

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“…This implies a distinct possibility that malignancy-induced changes in platelet homeostasis and activation can contribute to the overall tumor microenvironment whereby extrinsic remodeling of cell surface glycans alters the host antitumor response. Indeed, removal of sialic acids from immune cell surfaces such as dendritic cells results in their enhanced ability for anti-tumor activity (Silva et al 2016). By inference then, excessive sialylation, triggered by platelet activation, should impose a dampening of normal immune cell functions, leading to poorer outcomes in malignancies with thrombocytosis.…”

Section: Discussionmentioning

confidence: 99%

Circulating blood and platelets supply glycosyltransferases that enable extrinsic extracellular glycosylation

et al. 2016

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Glycosyltransferases, usually residing within the intracellular secretory apparatus, also circulate in the blood. Many of these blood-borne glycosyltransferases are associated with pathological states, including malignancies and inflammatory conditions. Despite the potential for dynamic modifications of glycans on distal cell surfaces and in the extracellular milieu, the glycan-modifying activities present in systemic circulation have not been systematically examined. Here, we describe an evaluation of blood-borne sialyl-, galactosyl-and fucosyltransferase activities that act upon the four common terminal glycan precursor motifs, GlcNAc monomer, Gal(β3)GlcNAc, Gal(β4)GlcNAc and Gal(β3)GalNAc, to produce more complex glycan structures. Data from radioisotope assays and detailed product analysis by sequential tandem mass spectrometry show that blood has the capacity to generate many of the well-recognized and important glycan motifs, including the Lewis, sialylLewis, H-and Sialyl-T antigens. While many of these glycosyltransferases are freely circulating in the plasma, human and mouse platelets are important carriers for others, including ST3Gal-1 and β4GalT. Platelets compartmentalize glycosyltransferases and release them upon activation. Human platelets are also carriers for large amounts of ST6Gal-1 and the α3-sialyl to Gal(β4)GlcNAc sialyltransferases, both of which are conspicuously absent in mouse platelets. This study highlights the capability of circulatory glycosyltransferases, which are dynamically controlled by platelet activation, to remodel cell surface glycans and alter cell behavior.

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Sialic acid removal from dendritic cells improves antigen cross-presentation and boosts anti-tumor immune responses

Cited by 39 publications

References 40 publications

Metabolic sialic acid blockade lowers the activation threshold of moDCs for TLR stimulation

Metabolic sialic acid blockade lowers the activation threshold of moDCs for TLR stimulation

MHC Class I Stability is Modulated by Cell Surface Sialylation in Human Dendritic Cells

Circulating blood and platelets supply glycosyltransferases that enable extrinsic extracellular glycosylation

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