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

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.

The involvement and application potential of exosomes in breast cancer immunotherapy

“…Some studies have found that circulating miR-20a-5p released by TNBC cells through exosomes promotes cancer cell growth by inducing cluster of differentiation 8 (CD8 + ) T cell dysfunction, leading to immunosuppression. Modulating miR-20a-5p could emerge as a novel approach to overcome the resistance of TNBC to anti-PD-1 immunotherapy ( 37 ).…”

Different origin-derived exosomes and their clinical advantages in cancer therapy

“…Exosomal miR-20a-5p is released by breast cancer cells and transferred to CD8 + T cells, where it inhibits their function by targeting the nuclear protein coactivator of histone transcription (NPAT) ( 347 ). NPAT is a cell cycle gene highly expressed in immature CD8 T cells, The miR-20a-5p binds to the 3’-UTR of NPAT, inducing the development of resistance to anti-PD-1 therapy.…”

“…NPAT is a cell cycle gene highly expressed in immature CD8 T cells, The miR-20a-5p binds to the 3’-UTR of NPAT, inducing the development of resistance to anti-PD-1 therapy. These findings suggest that exosomal miR-20a-5p derived from triple-negative breast cancer plays an important role in promoting immune escape and immunotherapy resistance by inducing CD8 + T cell dysfunction ( 347 ). Breast cancer-derived exosomes containing tumor cell-derived PD-L1 interact with PD-1-producing T cells to significantly reduce responses to immune checkpoint blockade agents.…”