Immune Checkpoint Therapy in Macrophage

Tumor-associated macrophages are an important part of the tumor microenvironment, and targeting their immune checkpoints has excellent anti-tumor potential, and they have emerged as potential targets in cancer therapy. Here, Creative Biolabs highlights some macrophage-associated immune checkpoint proteins, and related development services can be customized by contacting us.

Macrophage Immune Checkpoints

Macrophage function is tightly controlled by many negative regulators that directly inhibit or divert their effector functions. Some of these molecules, such as SIRPα, Siglec and members of the LILRB family are known as myeloid immune checkpoints. These pathways are physiologically used to protect host tissues from unwanted attacks, leading to a state of immunosuppression and activation of the trophic function of TAM tissues, which may ultimately be hijacked by tumor cells to evade recognition by the immune system and proliferation.

Fig. 1 Immune checkpoints expressed on macrophages. (Xu S, et al., 2023)

SIRPα/CD47

• CD47 is a transmembrane protein with glycosylation that is expressed in a variety of different cell types. It negatively regulates antitumor immunity by inhibiting phagocytosis and is involved in mediating cell proliferation, migration, apoptosis and immune homeostasis.
• SIRPα is the primary ligand for CD47. CD47 binds to SIRPα to form the CD47-SIRPα signaling complex, which leads to tyrosine phosphorylation on the intracellular ITIM motif. This signaling inhibits macrophage-mediated phagocytosis and protects normal cells from destruction by the immune system.

Several potential therapeutic agents have been developed to target CD47, including antibodies, small molecules, siRNAs and peptides.

Siglec Family

Siglecs are a family of receptors that bind to salivary acid-containing glycans, and 15 human and 9 murine Siglec molecules have been identified. Macrophages highly express several different Siglec receptors, including Siglec-3, Siglec-5, Siglec-7, Siglec9, Siglec-10, Siglec14, and Siglec-15.

Siglec molecules intracellularly contain immunoreceptor tyrosine inhibitory motifs (ITIM), which are usually components of those immunoreceptors that inhibit and suppress activating signals, thereby regulating the function of a wide range of immune cells.

LILRB Family

LILRB is a class of primary transmembrane glycoproteins that have immunoglobulin-like (Ig-like) structural domains in the extracellular region and ITIM motifs in the intracellular region.

• LILRB1 is an MHC-binding protein that is widely expressed on immune cells and enriched on TAMs. It contains ITIM motifs and transduces inhibitory signals.
• Macrophages also express LILRB2, which in solid tumors interacts with relevant ligands in the tumor microenvironment, HLA-G, ANGPTLs, SEMA4A, and CD1d, resulting in pro-tumorigenic growth of myeloid cells and enhancing tumor immune escape.

To aid in the development of immune checkpoint inhibitors, Creative Biolabs offers customized services to develop a range of high-quality macrophage immune checkpoint proteins, including CD47, SIRPα, CD24, Siglec-10, LILRBs, and others. Do not hesitate to contact us.

References

1. Xu S, et al. Targeting immune checkpoints on tumor-associated macrophages in tumor immunotherapy. Frontiers in Immunology, 2023, 14: 1199631.
2. Nakamura K and Smyth M J. Myeloid immunosuppression and immune checkpoints in the tumor microenvironment. Cellular & molecular immunology, 2020, 17(1): 1-12.

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