New immune checkpoint for cancer therapy: Siglec receptor
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New immune checkpoint for cancer therapy: Siglec receptor
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New immune checkpoint for cancer therapy: Siglec receptor.
Over the past decade, cancer immunotherapy in the form of immune checkpoint inhibitors and cell therapies has improved treatment and outcomes for many patients.
Despite this, most cancers remain resistant to currently approved cancer immunotherapies. New approaches and rational combinations are needed to overcome these resistances.
Interaction between sialic acid containing sialoglycans in the tumor microenvironment and sialic acid-binding immunoglobulin-like lectin ( Siglec ) receptors on tumor-infiltrating immune cells may represent a new immune checkpoint, recent studies suggest and potential new targets for 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 mouse Siglec molecules have been found so far.
Siglec receptors can be further divided into sequence-conserved receptors and rapidly evolving receptors related to CD33. Siglec-1, Siglec-2 ( CD22 ), Siglec-4, and Siglec-15 belong to a conserved family; Siglec-3 ( CD33 ), Siglec-5, Siglec-6, Siglec-7, Siglec8, Siglec-9, Sigle-c -11, Siglec-XII, Siglec-14, and Siglec-16 belong to the rapidly evolving CD33-related Siglecs receptors.
According to different intracellular signaling domains, Siglec receptors can also be divided into inhibitory, activating and non-signaling types. Siglec-11, Siglec-14, and Siglec-15 are activating Siglec receptors, while Siglec-1 and Siglec-4 have no direct immunomodulatory intracellular domains. All other human Siglec receptors are inhibitory in nature.
The Siglec family belongs to the type I membrane protein that penetrates the membrane once, and has very typical and conserved structural characteristics in structure.
Its membrane-penetrating region consists of 2 to 17 extracellular Ig domains, and the N-terminus is composed of a V- set Ig domain and a certain number of C2-set Ig domains.
Inhibitory Siglec receptor cells contain immunoreceptor tyrosine inhibition motif ( ITIM ) and immunoreceptor switch motif ( ITSM ) domains, which can regulate intracellular signaling through the participation of SHP1 and SHP2 phosphatases.
Therefore, inhibitory Siglecs can inhibit immune cell activation in a similar manner to PD-1/PD-L1. The activating Siglec receptor has a transmembrane domain with positively charged amino acids that mediates the recruitment of DAP12, which contains the immunoreceptor tyrosine-based activator, when the CRD binds to the sialoglycan ligand sequence ( ITAM ) and can deliver an activation signal.
Expression of cancer-associated Siglec ligands
Many studies have reported changes in the expression of sialoglycans in cancer and in the tumor microenvironment, and tumor cells are often hypersialylated, producing ligands for the inhibitory Siglec receptors on immune cells.
For example, pancreatic ductal adenocarcinoma ( PDAC ) tumor cells showed increased sialylation due to overexpression of the sialyltransferases ST3GAL1 and ST3GAL4 .
Sialylation of PDAC cells is recognized by Siglec-7 and Siglec-9 on myeloid cells and polarizes monocytes toward tumor-promoting macrophages. Likewise, upregulation of Siglec-9 ligands has been demonstrated in human colorectal, prostate, breast and non-small cell lung cancers.
Through genome-wide screening, sialylated CD43 has been identified as a highly specific ligand for Siglec-7, inhibiting NK cell-mediated killing of K562 leukemia cells.
LGALS3BP has been shown to be a secreted cancer-associated ligand of several Siglecs, including Siglec-9 , that inhibits neutrophil activation.
CD24 is overexpressed in many cancers and, through its interaction with Siglec-10 on tumor-associated macrophages ( TAMs ), serves as a major mechanism of immune evasion in certain ovarian and breast cancers.
Furthermore, soluble CD52 likewise binds to Siglec-10 on T cells, which has been reported to suppress T cells in autoimmune diseases.
Effects of Siglec receptors on cancer immune cells
Siglec receptors are widely expressed on different cells of the immune system. Functionally relevant interactions between sialoglycan ligands and Siglec receptors on different immune cells have been shown to contribute to the establishment of an immunosuppressive microenvironment in the context of cancer.
Innate immune cells, especially macrophages, highly express several different Siglec receptors, including Siglec-3, Siglec-5, Siglec-7, Siglec9, Siglec-10, Siglec/14, and Siglec-15.
It was recently demonstrated that sialoglycan binding to Siglec-7 and Siglec-9 in pancreatic cancer cells induces a tumor-promoting macrophage phenotype.
Furthermore, it has been shown that sialylated CD24 on cancer cells interacts with Siglec-10 on TAMs to inhibit phagocytosis.
Siglec-15 on macrophages has also been shown to suppress T cell-mediated antitumor immunity.
Dendritic cells are important mediators of anti-tumor immune responses and are closely related to the success of immunotherapy. Recent studies further suggest a role for Siglec receptors on classical dendritic cells ( cDC ).
Mouse Siglec-G on DCs has been shown to regulate antigen processing; moreover, Siglec-E in mice has been shown to be involved in antigen uptake and presentation to CD4+ T cells.
Antigen sialylation induces tolerogenic regulatory T cells via Siglec-E in a mouse model system.
Sialoglycans on human monocyte-derived dendritic cells inhibit immune cell activation through Siglec-7 and Siglec-9. Sialoglycans can also induce high-affinity interactions between DCs and CD8+ T cells.
NK cells are important innate lymphocytes. Several groups of studies have shown that Siglec-7 and Siglec-9 on NK cells can interact with cancer-associated sialoglycans and participate in the suppression of anti-tumor immune activation.
Insertion of synthetic sialoglycans into the membrane of tumor cells dose-dependently inhibited NK cell-mediated killing and degranulation.
Recent work has further demonstrated that Siglec-7 interacts with sialylated PSGL-1 on multiple myeloma cells to inhibit NK cell-mediated killing of myeloma cells.
Furthermore, overexpression of the ganglioside Siglec-7 ligand suppresses NK cell activation in renal carcinoma cells; sialylated MUC16 binds human Siglec-9 and suppresses NK cell activation in ovarian cancer.
In addition to affecting myeloid cells and other innate immune cells, the sialoglycan-Siglec interaction also affects the adaptive immune system in cancer.
The study found that Siglec-9 was upregulated in blood and tumor-infiltrating T cells of cancer patients, and it was expressed on tumor-specifically depleted PD-1+ T cells.
Reduction of Siglec-9 ligand on tumor cells significantly induces T cell-mediated effector function and tumor cell killing.
Siglec-5 and Siglec-10 were also found to be upregulated after acute activation of T cells and may affect antitumor immunity.
In conclusion, the interaction of sialoglycans with Siglec receptors has been shown to induce tumor-promoting phenotypes in tumor-associated macrophages, inhibit NK cell and neutrophil activation, reduce DC maturation and antigen presentation, and suppress T cell responses that contribute to the immunosuppressive tumor microenvironment.
Drug Development Targeting Sialoglycan-Siglec
In recent years, the Siglec receptor as a tumor antigen has been an important target for the treatment of cancer. Siglec-2 ( CD22 ) is expressed in many B-cell malignancies, and antibody-drug conjugates ( ADCs ) have been successfully used to target tumor cells, such as inotuzumab ozogamicin in relapsed acute lymphoblastic leukemia.
CAR-T cells targeting Siglec-2 and CD19 have also been developed to treat patients with relapsed diffuse large cell B-cell lymphoma or acute lymphoblastic leukemia.
In addition, ADCs targeting Siglec-3 are also being developed and tested.
In addition to being a direct tumor-associated antigen, the Siglec receptor and its sialoglycan ligand can also serve as a target to activate immune cells against tumors.
Siglec receptors can be blocked by high-affinity antibodies, similar to immune checkpoint inhibitors of PD-1/PD-L1 and CTLA-4.
The blocking antibody NC318 targets Siglec-15 and is currently being studied in combination with pembrolizumab in patients with advanced non-small cell lung cancer (NCT04699123 ) .
Siglec-7 and Siglec-9 are potential targets for enhancing the anti-tumor activity of NK cells.
A preclinical study using Siglec-7 and -9 blocking antibodies demonstrated anti-tumor efficacy in mouse models, blocking Inhibitory Siglec receptors may support repolarization of TAMs in immunosuppressive microenvironments and increase phagocytosis of antitumor macrophages.
Furthermore, the interaction between CD24 on tumor cells and Siglec-10 on tumor-associated macrophages is considered a new therapeutic target to enhance macrophage phagocytosis.
Another approach is to use blocking antibodies against specific carbohydrates. A recent study showed that antibodies against ganglioside GD2 can improve anti-tumor immunity by inhibiting the binding of GD2 to Siglec-7 on macrophages, thereby enhancing the effect of CD47 blockade by further increasing phagocytosis.
Furthermore, reducing sialoglycan density in tumor cells and in the tumor microenvironment is an alternative strategy. New inhibitors of sialic acid biosynthesis could be developed to improve cancer immunotherapy.
Inhibition of N-glycosylation of tumor cells using 2-deoxy-D-glucose increased CAR-T cell-mediated killing and efficacy in a mouse model. Using enzymes to reduce the density of sialoglycans in tumors has also been shown to enhance antitumor immunotherapy, and a bacterial sialidase conjugated to the anti-HER2 antibody trastuzumab is currently in first-in-human clinical trials.
Summary
Improvements in cancer immunotherapy require the development of new approaches.
The Siglec receptor and its interaction with sialoglycan ligands is a potential novel immune checkpoint for improved cancer immunotherapy.
Over the past few years, several preclinical and clinical studies have supported the development of drugs targeting the Siglec receptor.
Cancer immunotherapy targeting the sialoglycan -Siglec axis shows promising potential.
references:
1.Siglec receptors as new immune checkpoints in cancer. Mol Aspects Med.2022 Aug 7;101112.
New immune checkpoint for cancer therapy: Siglec receptor
(source:internet, reference only)
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