Siglec-9 Regulates an Effector Memory CD8+ T-cell Subset That Congregates in the Melanoma Tumor Microenvironment.
Cancer Immunol Res
; 7(5): 707-718, 2019 05.
Article
em En
| MEDLINE
| ID: mdl-30988027
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.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
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Pele
Base de dados:
MEDLINE
Assunto principal:
Antígenos CD
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Subpopulações de Linfócitos T
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Linfócitos T CD8-Positivos
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Microambiente Tumoral
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Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico
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Melanoma
Limite:
Humans
Idioma:
En
Revista:
Cancer Immunol Res
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Suíça