Sialylated glycoproteins suppress immune cell killing by binding to Siglec-7 and Siglec-9 in prostate cancer
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
- Jessica C. Stark (ORCID: https://orcid.org/0000-0003-3828-5438)
- Nicholas M. Riley (ORCID: https://orcid.org/0000-0002-1536-2966)
- Rosalie Nolley (ORCID: https://orcid.org/0009-0004-7269-5443)
- Xiangyue Zhang (ORCID: https://orcid.org/0000-0002-4517-6777)
- Sharon J. Pitteri (ORCID: https://orcid.org/0000-0002-3119-873X)
- Fernando Jose Garcia Marques
- Hongjuan Zhao (ORCID: https://orcid.org/0000-0001-6083-0370)
- James D. Brooks (ORCID: https://orcid.org/0000-0003-4521-7505)
- G. Edward Marti (ORCID: https://orcid.org/0000-0002-3390-436X)
- Edgar G. Engleman (ORCID: https://orcid.org/0000-0002-2096-9279)
- Aram Lyu (ORCID: https://orcid.org/0000-0003-3044-4887)
- Zenghua Fan (ORCID: https://orcid.org/0000-0002-5119-5296)
- Lawrence H. Fong (ORCID: https://orcid.org/0000-0002-6428-428X)
- Sarah M. Totten
- Carolyn R. Bertozzi (ORCID: https://orcid.org/0000-0003-4482-2754)
- Ru M. Wen (ORCID: https://orcid.org/0000-0002-4141-7377)
- Abel Bermudez (ORCID: https://orcid.org/0009-0002-3235-5538)
Institutions
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- Canary Institute of Cancer Research (ES)
- Parker Institute for Cancer Immunotherapy (US)
- Massachusetts Institute of Technology (US)
- Stanford University (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-10-22
- DOI
- https://doi.org/10.1172/jci180282
- Citations
- 32
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 7.48
Funders
- U.S. Department of Defense
- Peter Michael Foundation
- Society for Immunotherapy of Cancer
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- National Institutes of Health
- National Cancer Institute