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Immunotherapy with targeted therapeutic antibodies is often ineffective in long-term responses in cancer patients due to resistance mechanisms such as overexpression of checkpoint molecules. Similar to T lymphocytes, myeloid immune cells express inhibitory checkpoint receptors that interact with ligands overexpressed on cancer cells, contributing to treatment resistance. While CD47/SIRPα-axis inhibitors in combination with IgA therapy have shown promise, complete tumor eradication remains a challenge, indicating the presence of other checkpoints. We investigated hypersialylation on the tumor cell surface as a potential myeloid checkpoint and found that hypersialylated cancer cells inhibit neutrophil-mediated tumor killing through interactions with sialic acid-binding immunoglobulin-like lectins (Siglecs). To enhance antibody-dependent cellular cytotoxicity (ADCC) using IgA as therapeutic, we explored strategies to disrupt the interaction between tumor cell sialoglycans and Siglecs expressed on neutrophils. We identified Siglec-9 as the primary inhibitory receptor, with Siglec-7 also playing a role to a lesser extent. Blocking Siglec-9 enhanced IgA-mediated ADCC by neutrophils. Concurrent expression of multiple checkpoint ligands necessitated a multi-checkpoint-blocking approach. In certain cancer cell lines, combining CD47 blockade with desialylation improved IgA-mediated ADCC, effectively overcoming resistance that remained when blocking only one checkpoint interaction. Our findings suggest that a combination of CD47 blockade and desialylation may be necessary to optimize cancer immunotherapy, considering the upregulation of checkpoint molecules by tumor cells to evade immune surveillance.

Sialic Acids on Tumor Cells Modulate IgA Therapy by Neutrophils via Inhibitory Receptors Siglec-7 and Siglec-9