Introduction
The sialic acid-binding immunoglobulin type lectins (Siglecs) are a family of co-receptors that help regulate immune cell recognition of self. Most Siglecs contain cytoplasmic inhibitory immunoreceptor tyrosine-based inhibitory motifs (ITIM), characteristic of immune checkpoints that suppress cell signaling. Ligating these Siglecs is generally insufficient to elicit an inhibitory response. Rather, they must be recruited to the immune synapse adjacent to activating receptors, where their ITIM motifs can be phosphorylated, thereby recruiting phosphatases that shut down the signaling cascade. Utilizing this basic principle, we have exploited Siglecs to suppress unwanted immune responses, including suppression of B-cell responses to prevent the generation of unwanted anti-drug antibodies to biotherapeutics and preventing antibody-mediated autoimmune disease. The opposite direction is to prevent inhibitory responses of the Siglecs to enhance immune cell killing. Cancer cells that employ hyper-sialylation to evade immune cell attack are particularly relevant in this regard. One promising approach is to destroy siglec ligands to enhance immune responses. To this end we have developed several strategies to enhance immune responses to cancer by reducing hypersialylation in the tumor microenvironment.
Acknowledgement: This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) and Department of Defense (DOD).