ALK and RET Inhibitors Promote HLA Class I Antigen Presentation and Unmask New Antigens within the Tumor Immunopeptidome.
Cancer Immunol Res
; 7(12): 1984-1997, 2019 12.
Article
en En
| MEDLINE
| ID: mdl-31540894
ABSTRACT
T-cell immunotherapies are often thwarted by the limited presentation of tumor-specific antigens abetted by the downregulation of human leukocyte antigen (HLA). We showed that drugs inhibiting ALK and RET produced dose-related increases in cell-surface HLA in tumor cells bearing these mutated kinases in vitro and in vivo, as well as elevated transcript and protein expression of HLA and other antigen-processing machinery. Subsequent analysis of HLA-presented peptides after ALK and RET inhibitor treatment identified large changes in the immunopeptidome with the appearance of hundreds of new antigens, including T-cell epitopes associated with impaired peptide processing (TEIPP) peptides. ALK inhibition additionally decreased PD-L1 levels by 75%. Therefore, these oncogenes may enhance cancer formation by allowing tumors to evade the immune system by downregulating HLA expression. Altogether, RET and ALK inhibitors could enhance T-cell-based immunotherapies by upregulating HLA, decreasing checkpoint blockade ligands, and revealing new, immunogenic, cancer-associated antigens.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Antígenos de Histocompatibilidad Clase I
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Inhibidores de Proteínas Quinasas
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Proteínas Proto-Oncogénicas c-ret
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Quinasa de Linfoma Anaplásico
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Antígenos de Neoplasias
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Cancer Immunol Res
Año:
2019
Tipo del documento:
Article