Siglec-9 Regulates an Effector Memory CD8+ T-cell Subset That Congregates in the Melanoma Tumor Microenvironment
2019
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
effectormemory cells with high functional capacity and signatures of clonal expansion. This
cytotoxic T-cellsubset was functionally inhibited in the presence of
Siglec-9 ligands or by
Siglec-9 engagement by specific antibodies. TCR signaling pathways and key
effectorfunctions (cytotoxicity, cytokine production) of CD8 + T cells were suppressed by
Siglec-9 engagement, which was associated with the phosphorylation of the inhibitory
protein tyrosine phosphataseSHP-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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