Siglec Receptors in Tumor Immunity and Their Targeted Therapies

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Siglec Receptors in Tumor Immunity and Their Targeted Therapies

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Siglec Receptors in Tumor Immunity and Their Targeted Therapies

In the past decade, cancer immunotherapy in the form of immune checkpoint inhibitors and cell therapies has significantly improved the treatment and prognosis of many cancer patients.

However, the majority of cancers still exhibit resistance to currently approved cancer immunotherapies.

New approaches and rational combinations are needed to overcome these resistance mechanisms.

Recent research suggests that the interaction between sialic acid-containing polysaccharides in the tumor microenvironment and sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells may represent a novel immune checkpoint and potential target for cancer immunotherapy.

Siglec Receptors and Signaling Pathways

Siglecs constitute a family of receptors that bind to sialic acid-containing polysaccharides. Most Siglec receptors are inhibitory, with 15 human and 9 murine Siglec molecules identified to date. Siglec receptors can further be categorized into conserved and rapidly evolving receptors. Siglec-1, Siglec-2 (CD22), Siglec-4, and Siglec-15 belong to the conserved family, while Siglec-3 (CD33), Siglec-5, Siglec-6, Sigleg-7, Siglec-8, Siglec-9, Sigle-c-11, Siglec-XII, Siglec-14, and Siglec-16 are part of the rapidly evolving CD33-related Siglecs.

Based on the differences in intracellular signaling domains, Siglec receptors can be classified as inhibitory, activating, or non-signaling. Inhibitory Siglecs contain immunoreceptor tyrosine-based inhibitory motifs (ITIM) and immunoreceptor tyrosine-based switch motifs (ITSM) in their structural domains, allowing them to regulate intracellular signaling through phosphatases such as SHP1 and SHP2. As such, inhibitory Siglecs can inhibit immune cell activation in a manner similar to PD-1/PD-L1. Activating Siglec receptors possess transmembrane domains with positively charged amino acids, and upon binding to sialic acid-containing polysaccharide ligands, they recruit DAP12, which contains immunoreceptor tyrosine-based activation motifs (ITAM) and can transmit activating signals.

Expression of Cancer-Related Siglec

Ligands Numerous studies have reported changes in the expression of sialic acid-containing polysaccharides in cancer and the tumor microenvironment, with tumor cells often exhibiting heightened sialylation, resulting in the production of ligands for inhibitory Siglec receptors on immune cells. For instance, due to the overexpression of sialyltransferases ST3GAL1 and ST3GAL4, pancreatic ductal adenocarcinoma (PDAC) tumor cells display increased sialylation. The sialylation of PDAC cells is recognized by Siglec-7 and Siglec-9 on myeloid cells, leading to the polarization of monocytes towards pro-tumoral macrophages. Similarly, the upregulation of Siglec-9 ligands has been confirmed in human colorectal cancer, prostate cancer, breast cancer, and non-small cell lung cancer.

Through genome-wide screens, sialylated CD43 has been identified as a highly specific ligand for Siglec-7, inhibiting NK cell-mediated cytotoxicity against K562 leukemia cells. LGALS3BP has been shown to be a secreted cancer-associated ligand for several Siglecs, including Siglec-9, capable of suppressing neutrophil activation. CD24 is overexpressed in many cancers and is considered a major mechanism of immune evasion in certain ovarian and breast cancers due to its interaction with Siglec-10 on tumor-associated macrophages (TAMs). Additionally, soluble CD52 binds to Siglec-10 on T cells and is reported to inhibit T cell responses in autoimmune diseases.

Impact of Siglec Receptors on Cancer Immune Cells

Siglec receptors are widely expressed on various immune cells in the immune system. Evidence indicates that the functional interaction between sialic acid-containing polysaccharide ligands and Siglec receptors on different immune cells plays a role in establishing an immune-suppressive microenvironment in cancer.

Innate immune cells, especially macrophages, express several different Siglec receptors, including Siglec-3, Siglec-5, Siglec-7, Siglec-9, Siglec-10, Siglec/14, and Siglec-15. Recent studies have demonstrated that the binding of Siglec-7 and Siglec-9 to sialylated polysaccharides on pancreatic cancer cells induces a pro-tumoral macrophage phenotype. Moreover, it has been shown that the interaction between sialylated CD24 on cancer cells and Siglec-10 on TAMs can inhibit phagocytosis. Siglec-15 on macrophages has also been proven to suppress T cell-mediated anti-tumor immunity.

Dendritic cells are vital mediators of anti-tumor immune responses and are closely associated with the success of immunotherapies. Recent research further suggests the role of Siglec receptors on classical dendritic cells (cDCs). Mouse Siglec-G has been shown to regulate antigen processing on DCs, and Siglec-E in mice is involved in antigen uptake and presentation to CD4+ T cells. Sialylation of antigens in mice can induce tolerance through Siglec-E-mediated regulatory T cell induction. Human monocyte-derived dendritic cells are inhibited in immune cell activation by sialic acid-containing polysaccharides through Siglec-7 and Siglec-9. Sialic acid-containing polysaccharides also induce high-affinity interactions between DCs and CD8+ T cells.

NK cells are essential innate lymphocytes. Several studies suggest that Siglec-7 and Siglec-9 on NK cells can interact with cancer-associated sialic acid-containing polysaccharides, participating in the inhibition of anti-tumor immune activation. Inserting synthetic sialic acid-containing polysaccharides into the cell membrane of tumor cells can dose-dependently suppress NK cell-mediated cytotoxicity and degranulation. Recent work has further demonstrated the interaction between Siglec-7 and sialylated PSGL-1 on multiple myeloma cells, which can inhibit NK cell-mediated killing. Moreover, in renal cancer cells, the overexpression of ganglioside Siglec-7 ligands inhibits NK cell activation, while sialylated MUC16 binds to human Siglec-9, suppressing NK cell activity in ovarian cancer.

In addition to affecting myeloid cells and other innate immune cells, sialic acid-containing polysaccharide-Siglec interactions also impact cancer’s adaptive immune system. Studies have shown that Siglec-9 is upregulated in the blood and tumor-infiltrating T cells of cancer patients and is expressed on PD-1+ T cells specific to tumors. A decrease in Siglec-9 ligands on tumor cells significantly induces T cell-mediated effector functions and tumor cell killing. After T cell acute activation, Siglec-5 and Siglec-10 are also found to be upregulated and may influence anti-tumor immunity.

In summary, the interaction between sialic acid-containing polysaccharides and Siglec receptors has been shown to promote a pro-tumoral macrophage phenotype, inhibit NK cell and neutrophil activation, reduce dendritic cell maturation and antigen presentation, and suppress T cell responses, contributing to the immune-suppressive tumor microenvironment.

Drug Development Targeting Sialic Acid-Siglec Axis

In recent years, Siglec receptors, as tumor antigens, have been a critical target for cancer treatment. Siglec-2 (CD22) is expressed in many B-cell malignancies, and antibody-drug conjugates (ADCs) have been successfully employed to target tumor cells, as seen in the treatment of relapsed acute lymphoblastic leukemia with inotuzumab ozogamicin. CAR-T cells targeting Siglec-2 and CD19 have also been developed for the treatment of relapsed diffuse large B-cell lymphoma or acute lymphoblastic leukemia patients. Furthermore, ADCs targeting Siglec-3 are in the process of development and testing.

Apart from serving as direct tumor-related antigens, Siglec receptors and their sialic acid-containing polysaccharide ligands can also be targeted to activate immune cells against tumors. High-affinity antibodies can block Siglec receptors, similar to immune checkpoint inhibitors such as PD-1/PD-L1 and CTLA-4. The blocking antibody NC318, targeting Siglec-15, is currently under clinical investigation in combination with pembrolizumab for advanced non-small cell lung cancer patients (NCT04699123). Siglec-7 and Siglec-9 are potential targets for enhancing NK cell anti-tumor activity, and preclinical studies using Siglec-7 and -9 blocking antibodies have demonstrated anti-tumor efficacy in mouse models. Blocking inhibitory Siglec receptors can support the repolarization of TAMs in the immune-suppressive microenvironment, enhancing the phagocytic activity of anti-tumor macrophages. Additionally, the interaction between CD24 on tumor cells and Siglec-10 on tumor-associated macrophages is considered a novel therapeutic target for enhancing macrophage phagocytosis.

Another approach involves using blocking antibodies against specific carbohydrates. Recent research suggests that antibodies against ganglioside GD2 can enhance anti-tumor immunity by inhibiting the interaction between GD2 on macrophages and Siglec-7, thereby further increasing the efficacy of CD47 blockade. Lowering the density of sialic acid polysaccharides on tumor cells and in the tumor microenvironment is an alternative strategy. Novel sialic acid biosynthesis inhibitors can be developed to improve cancer immunotherapy. In mouse models, inhibiting N-glycosylation of tumor cells using 2-deoxy-D-glucose enhances the cytotoxicity and effectiveness of CAR-T cells. Enzymatic reduction of sialic acid polysaccharides in tumors has also been shown to enhance cancer immunotherapy, with a sialidase conjugated to the anti-HER2 antibody trastuzumab currently in its first human clinical trial.

Conclusion

Improvements in cancer immunotherapy necessitate the development of new approaches.

Siglec receptors and their interactions with sialic acid-containing polysaccharide ligands represent a potential new immune checkpoint for enhancing cancer immunotherapy.

In recent years, several preclinical and clinical studies have supported the development of drugs targeting Siglec receptors.

Cancer immunotherapy targeting the sialic acid-Siglec axis shows promise as a valuable addition to the arsenal of anti-cancer treatments.

Siglec Receptors in Tumor Immunity and Their Targeted Therapies

Reference:

1. Siglec receptors as new immune checkpoints in cancer. Mol Aspects Med. 2022 Aug 7;101112.

(source:internet, reference only)

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