Identification of non-mutated neoantigens presented by TAP-deficient tumors.
J Exp Med
; 215(9): 2325-2337, 2018 09 03.
Article
en En
| MEDLINE
| ID: mdl-30115740
ABSTRACT
Most T cell-based immunotherapies of cancer depend on intact antigen presentation by HLA class I molecules (HLA-I). However, defects in the antigen-processing machinery can cause downregulation of HLA-I, rendering tumor cells resistant to CD8+ T cells. Previously, we demonstrated that a unique category of cancer antigens is selectively presented by tumor cells deficient for the peptide transporter TAP, enabling a specific attack of such tumors without causing immunopathology in mouse models. With a novel combinatorial screening approach, we now identify 16 antigens of this category in humans. These HLA-A*0201 presented peptides do not derive from the mutanome of cancers, but are of "self" origin and therefore constitute universal neoantigens. Indeed, CD8+ T cells specific for the leader peptide of the ubiquitously expressed LRPAP1 protein recognized TAP-deficient, HLA-Ilow lymphomas, melanomas, and renal and colon carcinomas, but not healthy counterparts. In contrast to personalized mutanome-targeted therapies, these conserved neoantigens and their cognate receptors can be exploited for immune-escaped cancers across diverse histological origins.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antígeno HLA-A2
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Presentación de Antígeno
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Linfocitos T CD8-positivos
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Transportadoras de Casetes de Unión a ATP
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Escape del Tumor
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Proteína Asociada a Proteínas Relacionadas con Receptor de LDL
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Antígenos de Neoplasias
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Proteínas de Neoplasias
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Neoplasias
Tipo de estudio:
Diagnostic_studies
Límite:
Female
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Humans
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Male
Idioma:
En
Revista:
J Exp Med
Año:
2018
Tipo del documento:
Article
País de afiliación:
Países Bajos