Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment

Egan, Hannah; Treacy, Oliver; Lynch, Kevin; Leonard, Niamh; O’Malley, Grace; Reidy, Eileen; O’Neill, Anne; Corry, Shania M.; Veirman, Kim De; Vanderkerken, Karin; Egan, Laurence J.; Ritter, Thomas; Hogan, Aisling; Redmond, Keara L.; Li, Peng; Che, Jenny; Gatlin, Wayne; Jayaraman, Pushpa; Sheehan, Margaret; Canney, Aoife; Hynes, Seán O.; Kerr, Emma; Dunne, Philip D.; O’Dwyer, Michael; Ryan, Aideen E.

doi:10.1016/j.celrep.2023.112475

Cited by 31 publications

(9 citation statements)

References 75 publications

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“…Although our study focused on the effect of CAF sialylation on macrophage during their differentiation and polarization, sialic acids can also modify other immune cells through Siglec engagement. A recent study, in particular, demonstrated that stromal sialylation can impede T cell proliferation 67 . Furthermore, the engagement of Siglec-9 on CD8 + T cells has been shown to diminish TCR signaling and effector function 56 , 57 .…”

Section: Discussionmentioning

confidence: 99%

Pancreatic cancer-associated fibroblasts modulate macrophage differentiation via sialic acid-Siglec interactions

Boelaars,

Rodriguez,

Huinen

et al. 2024

Commun Biol

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Despite recent advances in cancer immunotherapy, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive due to an immunosuppressive tumor microenvironment, which is characterized by the abundance of cancer-associated fibroblasts (CAFs). Once identified, CAF-mediated immune inhibitory mechanisms could be exploited for cancer immunotherapy. Siglec receptors are increasingly recognized as immune checkpoints, and their ligands, sialic acids, are known to be overexpressed by cancer cells. Here, we unveil a previously unrecognized role of sialic acid-containing glycans on PDAC CAFs as crucial modulators of myeloid cells. Using multiplex immunohistochemistry and transcriptomics, we show that PDAC stroma is enriched in sialic acid-containing glycans compared to tumor cells and normal fibroblasts, and characterized by ST3GAL4 expression. We demonstrate that sialic acids on CAF cell lines serve as ligands for Siglec-7, -9, -10 and -15, distinct from the ligands on tumor cells, and that these receptors are found on myeloid cells in the stroma of PDAC biopsies. Furthermore, we show that CAFs drive the differentiation of monocytes to immunosuppressive tumor-associated macrophages in vitro, and that CAF sialylation plays a dominant role in this process compared to tumor cell sialylation. Collectively, our findings unravel sialic acids as a mechanism of CAF-mediated immunomodulation, which may provide targets for immunotherapy in PDAC.

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Section: Discussionmentioning

confidence: 99%

Pancreatic cancer-associated fibroblasts modulate macrophage differentiation via sialic acid-Siglec interactions

Boelaars,

Rodriguez,

Huinen

et al. 2024

Commun Biol

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“…Tumors dramatically remodel their cell surface glycosylation. It is now clear that a key role for these remodeled glycans is to facilitate immune evasion and tumor progression by engaging multiple broad classes of lectin immunoreceptors [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]37,38,[71][72][73][74][75][76][77][78][79] . Our chimeric AbLec molecules result in a gain-of-function: the ability to block glyco-immune checkpoints that represent an important mechanism of immune suppression and therapeutic resistance in cancer.…”

Section: Discussionmentioning

confidence: 99%

“…studies indicate that upregulation of cell-surface sialoglycans allows tumors to engage inhibitory Siglec receptors on immune cells and evade immune surveillance [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] . Taken together, glycoimmune checkpoints are emerging as attractive targets for cancer immunotherapy.…”

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confidence: 99%

“…This approach uniquely enables blockade of immunomodulatory glycans at nanomolar concentrations agnostic of their specific identities. We demonstrate proof-of-concept of the AbLec platform through the development and characterization of AbLecs combining tumor-targeting antibodies with decoy receptor domains from Siglecs-7 and -9, which have been shown to mediate immune suppression in multiple cancers [11][12][13][16][17][18][19][20][21][22][23][24][25][26][27] . We show that tumor-targeting AbLecs enhance antibody-dependent phagocytosis and cytotoxicity of cancer cells by multiple primary immune cell subsets compared to the parent monoclonal antibody.…”

mentioning

confidence: 99%

“…We show that the AbLec platform can be applied to target diverse tumor-associated antigens, including HER2, CD20, and EGFR, and cancer cells with varying levels of antigen expression. Further, we designed and validated dual blockade AbLecs that simultaneously block protein-based immune checkpoints (e.g., PD-1/PD-L1, CD47/SIRPα) as well as glyco-immune checkpoints known to play roles in cancer (e.g., Siglec-7 13,15,19,20,25 , galectin-9 37,38 ). We found that glyco-immune checkpoint blockade was synergistic with blockade of these established checkpoints.…”

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confidence: 99%

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Antibody-lectin chimeras for glyco-immune checkpoint blockade

Stark

Gray

Wisnovsky

et al. 2022

Preprint

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Despite the curative potential of checkpoint blockade immunotherapy, the majority of patients remain unresponsive to existing treatments. Glyco-immune checkpoints — interactions of cell-surface glycans with lectin, or glycan binding, immunoreceptors — have emerged as prominent mechanisms of immune evasion and therapeutic resistance in cancer. Here, we describe antibody-lectin chimeras (AbLecs), a modular platform for glyco-immune checkpoint blockade. AbLecs are bispecific antibody-like molecules comprising a tumor-targeting arm as well as a lectin ″decoy receptor″ domain that directly bind tumor glycans and block their ability to engage lectin receptors on immune cells. AbLecs elicited tumor killing in vitro via macrophage phagocytosis and NK cell and granulocyte cytotoxicity, matching or outperforming combinations of monospecific antibodies with lectin-blocking or glycan-disrupting therapies. Furthermore, AbLecs synergized with blockade of the ″don′t eat me″ signal CD47 for enhanced tumor killing. AbLecs can be readily designed to target numerous tumor-associated antigens and glyco-immune checkpoint ligands, and therefore represent a new modality for cancer immune therapy.

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Synthesis of α‐Hydroxy‐1,2,3‐Triazole‐linked Sialyltransferase Inhibitors and Evaluation of Selectivity Towards ST3GAL1, ST6GAL1 and ST8SIA2

Szabo,

Dobie,

Montgomery

et al. 2024

ChemMedChem

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Tumour‐derived sialoglycans, bearing the charged nonulosonic sugar sialic acid at their termini, play a critical role in tumour cell adhesion and invasion, as well as evading cell death and immune surveillance. Sialyltransferases (ST), the enzymes responsible for the biosynthesis of sialylated glycans, are highly upregulated in cancer, with tumour hypersialylation strongly correlated with tumour growth, metastasis and drug resistance. As a result, desialylation of the tumour cell surface using either targeted delivery of a pan‐ST inhibitor (or sialidase) or systemic delivery of a non‐toxic selective ST inhibitors are being pursued as potential new anti‐metastatic strategies against multiple cancers including pancreatic, ovarian, breast, melanoma and lung cancer. Herein, we have employed molecular modelling to give insights into the selectivity observed in a series of selective ST inhibitors that incorporate a uridyl ring in place of the cytidine of the natural donor (CMP‐Neu5Ac) and replace the charged phosphodiester linker of classical ST inhibitors with a neutral a‐hydroxy‐1,2,3‐triazole linker. The inhibitory activities of the nascent compounds were determined against recombinant human ST enzymes (ST3GAL1, ST6GAL1, ST8SIA2) showing promising activity and selectivity towards specific ST sub‐types. Our ST inhibitors are non‐toxic and show improved synthetic accessibility and drug‐likeness compared to earlier nucleoside‐based ST inhibitors.

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Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment

Cited by 31 publications

References 75 publications

Pancreatic cancer-associated fibroblasts modulate macrophage differentiation via sialic acid-Siglec interactions

Pancreatic cancer-associated fibroblasts modulate macrophage differentiation via sialic acid-Siglec interactions

Antibody-lectin chimeras for glyco-immune checkpoint blockade

Synthesis of α‐Hydroxy‐1,2,3‐Triazole‐linked Sialyltransferase Inhibitors and Evaluation of Selectivity Towards ST3GAL1, ST6GAL1 and ST8SIA2

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