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

Cancer Immunol Res. 2019 May;7(5):707-718. doi: 10.1158/2326-6066.CIR-18-0505. Epub 2019 Apr 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

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