Siglec-9 Regulates an Effector Memory CD8+ T-cell Subset That Congregates in the Melanoma Tumor Microenvironment.

Abstract

Emerging evidence suggests an immunosuppressive role of altered tumor glycosylation due to downregulation of innate immune responses via immunoregulatory Siglecs. In contrast, human T cells, a major anticancer effector cell, only rarely express Siglecs. However, here, we report that the majority of intratumoral, but not peripheral blood, cytotoxic CD8+ T cells expressed Siglec-9 in melanoma. We identified Siglec-9+ CD8+ T cells as a subset of effector memory cells with high functional capacity and signatures of clonal expansion. This cytotoxic T-cell subset was functionally inhibited in the presence of Siglec-9 ligands or by Siglec-9 engagement by specific antibodies. TCR signaling pathways and key effector functions (cytotoxicity, cytokine production) of CD8+ T cells were suppressed by Siglec-9 engagement, which was associated with the phosphorylation of the inhibitory protein tyrosine phosphatase SHP-1, but not SHP-2. Expression of cognate Siglec-9 ligands was observed on the majority of tumor cells in primary and metastatic melanoma specimens. Targeting the tumor-restricted, glycosylation-dependent Siglec-9 axis may unleash this intratumoral T-cell subset, while confining T-cell activation to the tumor microenvironment.

• Authors: Quentin Haas, Kayluz Frias Boligan, Camilla Jandus, Christoph Schneider, Cedric Simillion, Michal A Stanczak, Monika Haubitz, Seyed Morteza Seyed Jafari, Alfred Zippelius, Gabriela M Baerlocher, Heinz Läubli, Robert E Hunger, Pedro Romero, Hans-Uwe Simon, Stephan von Gunten
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 7 Issue 5 Pg. 707-718 (05 2019) ISSN: 2326-6074 [Electronic] United States
• PMID: 30988027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antigens, CD
• SIGLEC9 protein, human
• Sialic Acid Binding Immunoglobulin-like Lectins

Topics

• Antigens, CD (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Humans
• Melanoma (immunology)
• Sialic Acid Binding Immunoglobulin-like Lectins (immunology)
• T-Lymphocyte Subsets (immunology)
• Tumor Microenvironment (immunology)