Cancer cell-derived exosomal miR-20a-5p inhibits CD8+ T-cell function and confers anti-programmed cell death 1 therapy resistance in triple-negative breast cancer.
Cancer Sci
; 115(2): 347-356, 2024 Feb.
Article
em En
| MEDLINE
| ID: mdl-38129137
ABSTRACT
Circulating miRNAs (cirmiRNAs) can be packaged into the exosomes, participating in intercellular communication, which affects the malignant progression and therapy resistance of triple-negative breast cancer (TNBC). Currently, immune checkpoint inhibitors that regulate T-cell function, especially antibodies against programmed cell death 1 (PD-1) or its ligand PD-L1, are emerging as new promising therapy for TNBC patients. However, only very limited patients showed complete or partial response to anti-PD-1 treatment. Dysfunction of CD8+ T cells is one of the key reasons for the immune escape of TNBC. The regulation of exosome-derived cirmiRNAs on CD8+ T cells in TNBC deserves more investigation. Here, the cirmiR-20a-5p level was significantly upregulated in the plasma of TNBC patients and culture supernatant of TNBC cells. High abundance of cirmiR-20a-5p was correlated with a worse prognosis of TNBC. cirmiR-20a-5p was secreted in the form of exosomes by TNBC cells. Exosomal cirmiR-20a-5p was internalized into CD8+ T cells and resulted into the dysfunction of CD8+ T. A mechanism study uncovered that cirmiR-20a-5p targeted the nuclear protein ataxia-telangiectasia (NPAT) and decreased NPAT expression in CD8+ T cells. An in vivo xenograft mouse model showed that cirmiR-20a-5p conferred TNBC to anti-PD-1 treatment resistance. Collectively, these findings indicated that cirmiR-20a-5p released by TNBC cells via exosome promotes cancer cell growth and leads to the immunosuppression by inducing CD8+ T cell dysfunction. This study suggests that targeting cirmiR-20a-5p might be a novel strategy for overcoming the resistance of TNBC to anti-PD-1 immunotherapy.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
MicroRNAs
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Neoplasias de Mama Triplo Negativas
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Sci
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Cancer sci
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Cancer science (Online)
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China