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

Haas, Quentin; Frias Boligan, Kayluz; Jandus, Camilla; Schneider, Christoph; Simillion, Cedric; Stanczak, Michal A; Haubitz, Monika; Jafari, Morteza; Zippelius, Alfred; Baerlocher, Gabriela M.; Läubli, Heinz; Hunger, Robert E.; Romero, Pedro; Simon, Hans-Uwe; von Gunten, Stephan (2019). Siglec-9 Regulates an Effector Memory CD8 T-cell Subset That Congregates in the Melanoma Tumor Microenvironment. Cancer immunology research, 7(5), pp. 707-718. American Association for Cancer Research 10.1158/2326-6066.CIR-18-0505

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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.

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