Sialylated glycoproteins suppress immune cell killing by binding to Siglec-7 and Siglec-9 in prostate cancer

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Abstract

Prostate cancer is the second leading cause of male cancer death in the U.S. Current immune checkpoint inhibitor–based immunotherapies have improved survival for many malignancies; however, they have failed to prolong survival for prostate cancer. Siglecs (sialic acid–binding immunoglobulin-like lectins) are expressed on immune cells and regulate their function. Siglec-7 and Siglec-9 contribute to immune evasion in cancer by interacting with sialic acid–containing glycoprotein ligands on cancer cells. However, the role of Siglec-7/9 receptors and their ligands in prostate cancer remains poorly understood. Here, we find that Siglec-7 and Siglec-9 are associated with poor prognosis in patients with prostate cancer and are highly expressed in myeloid cells, including macrophages, in prostate tumor tissues. Siglec-7 and -9 ligands were expressed in prostate cancer cells and human prostate tumor tissues. Blocking the interactions between Siglec-7/9 and sialic acids inhibited prostate cancer xenograft growth and increased immune cell infiltration in humanized mice in vivo. Using a CRISPRi screen and mass spectrometry, we identified CD59 as a candidate Siglec-9 ligand in prostate cancer. The identification of Siglec-7 and -9 as potential therapeutic targets, including the CD59/Siglec-9 axis, opens up opportunities for immune-based interventions in prostate cancer.

Authors

Ru M. Wen, Jessica C. Stark, G. Edward W. Marti, Zenghua Fan, Aram Lyu, Fernando Jose Garcia Marques, Xiangyue Zhang, Nicholas M. Riley, Sarah M. Totten, Abel Bermudez, Rosalie Nolley, Hongjuan Zhao, Lawrence Fong, Edgar G. Engleman, Sharon J. Pitteri, Carolyn R. Bertozzi, James D. Brooks