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Proc Natl Acad Sci U S A ; 116(47): 23662-23670, 2019 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-31685621

RESUMEN

The impact of intratumoral heterogeneity (ITH) and the resultant neoantigen landscape on T cell immunity are poorly understood. ITH is a widely recognized feature of solid tumors and poses distinct challenges related to the development of effective therapeutic strategies, including cancer neoantigen vaccines. Here, we performed deep targeted DNA sequencing of multiple metastases from melanoma patients and observed ubiquitous sharing of clonal and subclonal single nucleotide variants (SNVs) encoding putative HLA class I-restricted neoantigen epitopes. However, spontaneous antitumor CD8+ T cell immunity in peripheral blood and tumors was restricted to a few clonal neoantigens featuring an oligo-/monoclonal T cell-receptor (TCR) repertoire. Moreover, in various tumors of the 4 patients examined, no neoantigen-specific TCR clonotypes were identified despite clonal neoantigen expression. Mature dendritic cell (mDC) vaccination with tumor-encoded amino acid-substituted (AAS) peptides revealed diverse neoantigen-specific CD8+ T responses, each composed of multiple TCR clonotypes. Isolation of T cell clones by limiting dilution from tumor-infiltrating lymphocytes (TILs) permitted functional validation regarding neoantigen specificity. Gene transfer of TCRαß heterodimers specific for clonal neoantigens confirmed correct TCR clonotype assignments based on high-throughput TCRBV CDR3 sequencing. Our findings implicate immunological ignorance of clonal neoantigens as the basis for ineffective T cell immunity to melanoma and support the concept that therapeutic vaccination, as an adjunct to checkpoint inhibitor treatment, is required to increase the breadth and diversity of neoantigen-specific CD8+ T cells.


Asunto(s)
Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Subgrupos de Linfocitos T/inmunología , Sustitución de Aminoácidos , Antígenos de Neoplasias/genética , Vacunas contra el Cáncer/inmunología , Células Clonales , ADN de Neoplasias/genética , Células Dendríticas/inmunología , Antígenos HLA/inmunología , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Melanoma/genética , Melanoma/secundario , Polimorfismo de Nucleótido Simple , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Neoplasias Retroperitoneales/inmunología , Neoplasias Retroperitoneales/secundario , Análisis de Secuencia de ADN , Especificidad del Receptor de Antígeno de Linfocitos T , Escape del Tumor , Vacunación
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