Siglec-9 regulates an effector memory CD8+ T-cell subset that congregates in the melanoma tumor microenvironment

Quentin Haas, Kayluz Frias Boligan, Camilla Jandus, Christoph Schneider, Cedric Simillion, Michal A Stanczak, Monika Haubitz, S. Morteza Seyed Jafari, Alfred Zippelius, Gabriela M. Baerlocher, Heinz Läubli, Robert E Hunger (+3 others)
2019 Cancer immunology research  
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
more » ... nd 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.
doi:10.1158/2326-6066.cir-18-0505 pmid:30988027 fatcat:7ky3miqu7fhd5gmsd6bzam2mpm