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J Clin Invest ; 124(5): 2246-59, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24667641

RESUMO

Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can mediate regression of metastatic melanoma; however, TILs are a heterogeneous population, and there are no effective markers to specifically identify and select the repertoire of tumor-reactive and mutation-specific CD8⁺ lymphocytes. The lack of biomarkers limits the ability to study these cells and develop strategies to enhance clinical efficacy and extend this therapy to other malignancies. Here, we evaluated unique phenotypic traits of CD8⁺ TILs and TCR ß chain (TCRß) clonotypic frequency in melanoma tumors to identify patient-specific repertoires of tumor-reactive CD8⁺ lymphocytes. In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8⁺ TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8⁺ lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137). TCRß deep sequencing revealed oligoclonal expansion of specific TCRß clonotypes in CD8⁺PD-1⁺ compared with CD8⁺PD-1- TIL populations. Furthermore, the most highly expanded TCRß clonotypes in the CD8⁺ and the CD8⁺PD-1⁺ populations recognized the autologous tumor and included clonotypes targeting mutated antigens. Thus, in addition to the well-documented negative regulatory role of PD-1 in T cells, our findings demonstrate that PD-1 expression on CD8⁺ TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD-1 expression in the tumor microenvironment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Microambiente Tumoral/imunologia , Transferência Adotiva , Antígenos CD/genética , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Feminino , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Melanoma/terapia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Receptor de Morte Celular Programada 1/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Microambiente Tumoral/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Proteína do Gene 3 de Ativação de Linfócitos
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