New Immune Checkpoint for Cancer Therapy: Siglec Receptor

Recent studies suggest that the interaction between sialic acid containing sialoglycans in the tumor microenvironment and the sialic acid-binding immunoglobulin-like lectin (Siglec) receptor on tumor-infiltrating immune cells may represent a new immune checkpoint for cancer immunotherapy.

Here, Creative Biolabs delves into the intricacies of Siglec receptors and explores their potential as a novel target in cancer immunotherapy.

Siglec Receptors and Signaling Pathways

Siglecs are a family of receptors that bind to sialic acid-containing glycans. Most Siglec receptors are inhibitory and 15 human and 9 murine Siglec molecules have been identified. Siglec receptors can be further divided into sequence conserved receptors and rapidly evolving receptors associated with CD33. Siglec receptors can also be classified as inhibitory, activating and non-signaling depending on the intracellular signaling structural domain.

Fig. 1 Comparison of the Siglec-sialoglycan and PD-1/PD-L1 immune checkpoints. (Stanczak M A and Läubli H, 2023)

Inhibitory Siglecs can inhibit immune cell activation in a similar manner to PD-1/PD-L1. Activated Siglec receptors have a transmembrane structural domain of positively charged amino acids that mediates the recruitment of DAP12, which contains the immunoreceptor tyrosine-based activation motif (ITAM), when CRD binds to sialic acid glycan ligands and can transmit activation signals.

Expression of Cancer-Associated Siglec Ligands

Many studies have reported changes in the expression of sialoglycans in cancer and tumor microenvironment, and tumor cells are usually hyper-sialylated, producing ligands for inhibitory Siglec receptors on immune cells.

• Through genome-wide screens, sialylated CD43 has been identified as a highly specific ligand for Siglec-7 that inhibits NK cell-mediated killing of K562 leukemia cells.
• LGALS3BP has been shown to be a secreted cancer-associated ligand for several Siglecs, including Siglec-9, and inhibits neutrophil activation.
• CD24 is overexpressed in many cancers and is a major mechanism of immune evasion in some ovarian and breast cancers through interaction with Siglec-10 on tumor-associated macrophages (TAMs).
• Soluble CD52 similarly binds to Siglec-10 on T cells and has been reported to suppress T cells in autoimmune diseases.

Effect of Siglec Receptors on Cancer Immune Cells

Siglec receptors are widely expressed on different cells of the immune system. The interaction of sialoglycans with Siglec receptors has been shown to contribute to the immunosuppressive tumor microenvironment by inducing a pro-oncogenic phenotype of tumor-associated macrophages, inhibiting NK cell and neutrophil activation, reducing DC maturation and antigen presentation, and suppressing T cell responses.

• Intrinsic immune cells, particularly macrophages, are highly expressed in several different Siglec receptors, including Siglec-3, Siglec-5, Siglec-7, Siglec9, Siglec-10, Siglec/14, and Siglec-15.
• Dendritic cells are important mediators of antitumor immune responses. Sialoglycans on human monocyte-derived dendritic cells inhibit immune cell activation via Siglec-7 and Siglec-9.
• NK cells are important innate lymphocytes. Siglec-7 and Siglec-9 on NK cells can interact with cancer-associated sialoglycans and participate in the suppression of antitumor immune activation.

Drug Development Targeting Siglec

• Siglec receptors as tumor antigens have been important targets for the treatment of cancer. ADCs targeting Siglec-2 and CD22, CAR-T cells targeting Siglec-2 and CD19, and ADCs targeting Siglec-3 are all under development and testing.
• In addition to acting as a direct tumor-associated antigen, the Siglec receptor and its sialoglycan ligand can also be used as a target to activate immune cells against tumors.
• Another approach is to use blocking antibodies against specific glycans.

The identification of Siglec receptors as a novel immune checkpoint opens up exciting possibilities for cancer therapy. Creative Biolabs hopes to witness the translation of Siglec-based therapies from the laboratory to the clinic, offering new hope for patients in their fight against cancer.

Reference

1. Stanczak M A and Läubli H. Siglec receptors as new immune checkpoints in cancer. Molecular Aspects of Medicine, 2023, 90: 101112.

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