Aptamer‐Assisted Blockade of the Immune Suppressor Sialic Acid‐Binding Immunoglobulin‐Like Lectin‐15 for Cancer Immunotherapy

Abstract The percentage of low response and adaptive resistance to current antibody‐based immune checkpoint blockade (ICB) therapy requires the development of novel immunotherapy strategies. Here, we developed an aptamer‐assisted immune checkpoint blockade (Ap‐ICB) against sialic acid‐binding immunoglobulin‐like lectin‐15 (Siglec‐15), a novel immune suppressor broadly upregulated on cancer cells and tumor infiltrating myeloid cells, which is mutually exclusive of programmed cell death ligand 1 (PD‐L1). Using protein aptamer selection, we identified WXY3 aptamer with high affinity against Siglec‐15 protein/Siglec‐15 positive cells. We demonstrated that WXY3 aptamer rescued antigen‐specific T cell responses in vitro and in vivo. Importantly, the WXY3 Ap‐ICB against Siglec‐15 amplified anti‐tumor immunity in the tumor microenvironment and inhibited tumor growth/metastasis in syngeneic mouse model, which may result from enhanced macrophage and T cell functionality. In addition, by using aptamer‐based spherical nucleic acids, we developed a synergetic ICB strategy of multivalent binding and steric hindrance, which further improves the in vivo anti‐tumor effect. Taken together, our results support Ap‐ICB targeted Siglec‐15 as a potential strategy for normalization cancer immunotherapy.