Tumors use cell surface sialosides as a primary axis of immune regulation to avoid being destroyed by innate and adaptive immune systems. Therefore, therapeutic approaches that focus on tumor-associated sialosides may enhance antitumor immunity. Off-target desialylation may reveal cryptic sugars that activate different immune receptors, despite the fact that sialidase-based systems are promising therapeutic approaches to target malignancy. The blockade is not a possibility for Siglecs with poorly defined ligands. Instead, complete desialylation can prevent Siglec interactions.
Hypersialylated glycans interact with natural killer cells (NK) inhibitory receptors in cancer cells that overexpress sialic acid, preventing NK cell activation. An antibody-sialidase conjugate (T-Sia) that removes cell-surface sialic acids reduces the interaction between sialylated glycans and NK-inhibitory Siglec receptors and increases the binding between NK-activating NKG2D receptor and its ligands, increasing the susceptibility of tumor cells to NK cell-mediated ADCC.
Fig.1 A glycocalyx approach to cancer immunotherapy targeting the sialic acid axis of immune modulation. (Xiao, et al., 2016)
Desialylation increased immune cell infiltration and activation and prolonged mouse life in syngeneic breast cancer models; this effect was reliant on the expression of the Siglec-E checkpoint receptor present on tumor-infiltrating myeloid cells. Recent research also suggests that the removal of surface sialic acid increases the rate of internalization of ADCs and that targeted desialylation may increase their cytotoxic effects. Siglec receptors are expressed in a wide variety of innate tissues. Among the larger arsenal of new anticancer medicines coming toward clinical translation, glycan-editing antibody therapeutics will prove to be a powerful weapon.
Fig.2 Targeted desialylation of Siglec ligands with the antibody–enzyme conjugate T-Sia 2 as a modality for immune therapy. (Gray, et al., 2020)
Gray recently created T-Sia 2.0, a newer, more compact version of trastuzumab-sialidase conjugate (T-Sia). An undesired Tras-independent activity was seen in the earlier T-Sia. A sialidase from Salmonella typhimurium is used in T-Sia 2.0, which drastically lowers Tras-independent cell desialylation. This significantly increased T-Sia 2.0's cytotoxicity and selectivity. Similar to T-Sia, T-Sia 2.0 attaches to HER2 in the immune synapse, where it releases sialic acids from sialylated proteins and lipids. By doing this, it prevents Siglecs on immune cells from attaching and restores the connection of NK cell-activating receptors like NKG2D with their ligands. As a result, SHP1/2 is not drawn to the ITIM and ITSM domains of Siglecs, and the activity of immune cells is not suppressed. T-Sia 2.0 therapy increased immune cell infiltration and activation, inhibited tumor development, and prolonged survival. Therefore, it was shown that targeted desialylation of cancer cells was a promising method for evading glycol-immune checkpoints in vivo.
Fig.3 Siglecs and sialic acid in immune system regulation and specific targeting of the cancer sialome for treatment strategies. (Möckl, 2020)
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