TIGIT and PD-1 impair tumor antigen-specific CD8⺠T cells in melanoma patients.
J Clin Invest
; 125(5): 2046-58, 2015 May.
Article
em En
| MEDLINE
| ID: mdl-25866972
ABSTRACT
T cell Ig and ITIM domain (TIGIT) is an inhibitory receptor expressed by activated T cells, Tregs, and NK cells. Here, we determined that TIGIT is upregulated on tumor antigen-specific (TA-specific) CD8⺠T cells and CD8⺠tumor-infiltrating lymphocytes (TILs) from patients with melanoma, and these TIGIT-expressing CD8⺠T cells often coexpress the inhibitory receptor PD-1. Moreover, CD8⺠TILs from patients exhibited downregulation of the costimulatory molecule CD226, which competes with TIGIT for the same ligand, supporting a TIGIT/CD226 imbalance in metastatic melanoma. TIGIT marked early T cell activation and was further upregulated by T cells upon PD-1 blockade and in dysfunctional PD-1âºTIM-3⺠TA-specific CD8⺠T cells. PD-1âºTIGITâº, PD-1â»TIGITâº, and PD-1âºTIGITâ» CD8⺠TILs had similar functional capacities ex vivo, suggesting that TIGIT alone, or together with PD-1, is not indicative of T cell dysfunction. However, in the presence of TIGIT ligand-expressing cells, TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of both TA-specific CD8⺠T cells and CD8⺠TILs. Collectively, our results show that TIGIT and PD-1 regulate the expansion and function of TA-specific CD8⺠T cells and CD8⺠TILs in melanoma patients and suggest that dual TIGIT and PD-1 blockade should be further explored to elicit potent antitumor CD8⺠T cell responses in patients with advanced melanoma.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores Imunológicos
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Linfócitos do Interstício Tumoral
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Linfócitos T CD8-Positivos
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Receptor de Morte Celular Programada 1
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Melanoma
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Antígenos de Neoplasias
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Proteínas de Neoplasias
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2015
Tipo de documento:
Article