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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.
- Source :
-
Cancer science [Cancer Sci] 2024 Feb; Vol. 115 (2), pp. 347-356. Date of Electronic Publication: 2023 Dec 21. - Publication Year :
- 2024
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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 <superscript>+</superscript> T cells is one of the key reasons for the immune escape of TNBC. The regulation of exosome-derived cirmiRNAs on CD8 <superscript>+</superscript> 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 <superscript>+</superscript> T cells and resulted into the dysfunction of CD8 <superscript>+</superscript> T. A mechanism study uncovered that cirmiR-20a-5p targeted the nuclear protein ataxia-telangiectasia (NPAT) and decreased NPAT expression in CD8 <superscript>+</superscript> 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 <superscript>+</superscript> 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.<br /> (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Subjects :
- Humans
Animals
Mice
CD8-Positive T-Lymphocytes metabolism
Cell Line, Tumor
Cell Proliferation physiology
B7-H1 Antigen genetics
MicroRNAs genetics
MicroRNAs metabolism
Triple Negative Breast Neoplasms drug therapy
Triple Negative Breast Neoplasms genetics
Triple Negative Breast Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1349-7006
- Volume :
- 115
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cancer science
- Publication Type :
- Academic Journal
- Accession number :
- 38129137
- Full Text :
- https://doi.org/10.1111/cas.16036