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Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma.
Spranger, Stefani; Luke, Jason J; Bao, Riyue; Zha, Yuanyuan; Hernandez, Kyle M; Li, Yan; Gajewski, Alexander P; Andrade, Jorge; Gajewski, Thomas F.
Afiliação
  • Spranger S; Department of Pathology, University of Chicago, Chicago, IL 60637.
  • Luke JJ; Department of Medicine, University of Chicago, Chicago, IL 60637.
  • Bao R; Center for Research Informatics, University of Chicago, Chicago, IL 60637.
  • Zha Y; Human Immune Monitoring Facility, University of Chicago, Chicago, IL 60637.
  • Hernandez KM; Center for Research Informatics, University of Chicago, Chicago, IL 60637.
  • Li Y; Center for Research Informatics, University of Chicago, Chicago, IL 60637.
  • Gajewski AP; Center for Research Informatics, University of Chicago, Chicago, IL 60637.
  • Andrade J; Center for Research Informatics, University of Chicago, Chicago, IL 60637.
  • Gajewski TF; Department of Pathology, University of Chicago, Chicago, IL 60637; tgajewsk@medicine.bsd.uchicago.edu.
Proc Natl Acad Sci U S A ; 113(48): E7759-E7768, 2016 11 29.
Article em En | MEDLINE | ID: mdl-27837020
Melanoma metastases can be categorized by gene expression for the presence of a T-cell-inflamed tumor microenvironment, which correlates with clinical efficacy of immunotherapies. T cells frequently recognize mutational antigens corresponding to nonsynonymous somatic mutations (NSSMs), and in some cases shared differentiation or cancer-testis antigens. Therapies are being pursued to trigger immune infiltration into non-T-cell-inflamed tumors in the hope of rendering them immunotherapy responsive. However, whether those tumors express antigens capable of T-cell recognition has not been explored. To address this question, 266 melanomas from The Cancer Genome Atlas (TCGA) were categorized by the presence or absence of a T-cell-inflamed gene signature. These two subsets were interrogated for cancer-testis, differentiation, and somatic mutational antigens. No statistically significant differences were observed, including density of NSSMs. Focusing on hypothetical HLA-A2+ binding scores, 707 peptides were synthesized, corresponding to all identified candidate neoepitopes. No differences were observed in measured HLA-A2 binding between inflamed and noninflamed cohorts. Twenty peptides were randomly selected from each cohort to evaluate priming and recognition by human CD8+ T cells in vitro with 25% of peptides confirmed to be immunogenic in both. A similar gene expression profile applied to all solid tumors of TCGA revealed no association between T-cell signature and NSSMs. Our results indicate that lack of spontaneous immune infiltration in solid tumors is unlikely due to lack of antigens. Strategies that improve T-cell infiltration into tumors may therefore be able to facilitate clinical response to immunotherapy once antigens become recognized.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Cutâneas / Linfócitos T / Linfócitos do Interstício Tumoral / Melanoma / Antígenos de Neoplasias Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Cutâneas / Linfócitos T / Linfócitos do Interstício Tumoral / Melanoma / Antígenos de Neoplasias Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2016 Tipo de documento: Article