Siglec-7/9 are novel immune checkpoints for prostate cancer

Abstract Immune checkpoint-based therapy has led to striking improvements in survival in some types of cancer, but it is ineffective for others, including prostate cancer. Changes in glycosylation, particularly hypersialylation, have been found in diverse malignancies. Glycosylation can result in immune evasion through direct interactions of sialylated glycoproteins on cancer cell surfaces with Siglecs on immune cells including T cells, NK cells, and dendritic cells. Interactions between Siglec-7/9 and sialic acid have been implicated in inhibiting immune response in melanoma, leukemia, and lung cancer. Here, we found that Siglec-7/9 was highly expressed in immune cells including T cells and myeloid cells in the prostate cancer TCGA dataset. Immunohistochemistry demonstrated that Siglec-7/9 ligands were highly expressed in surgically resected prostate cancer tumor tissues but showed no or low expression in adjacent normal tissues. Siglec-7/9 ligands were also found in the prostate cancer cell lines. The disruption of Siglec-7/9 and their ligands by sialidase, which cleaves the sialic acid, or by anti-Siglec-7/9 blocking antibodies, promoted T cell-mediated cytotoxic killing of prostate cancer cells. Furthermore, anti-Siglec-7/9 treatment suppressed prostate cancer tumor growth in a humanized mouse model. Immunohistochemistry demonstrated that prostate cancers in mice treated with anti-Siglec 7/9 antibodies exhibited less Ki67 and CD31, and more cleaved caspase 3 and CD8 compared with the isotype control. This study provides insight into Siglec-7/9-sialic acid targeting strategies for prostate cancer and lays the groundwork for developing a novel class of immunotherapy-based drugs. Supported by grants from DoD (W81XWH2110195) and NIH (#LINK#U01CA226051#ENDLINK#)