Purpose: One of the most catastrophic malignant tumors is triple negative breast cancer (TNBC). It is characterized by rapid progression in the clinic. CircRNAs are abnormally expressed in almost all cancers and play important roles in tumor immune evasion. Nevertheless, the biological roles of the circular fibroblast growth factor receptor 4 RNA (circFGFR4) in TNBC remain unclear.
Methods: The expression of circFGFR4 in TNBC tissues and paired nontumor tissues was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The role of circFGFR4 in TNBC immune evasion was estimated by analyzing clinical tissues. In vivo circRNA precipitation, RNA immunoprecipitation, and luciferase reporter assays were performed to explore interaction between circFGFR4 and miR-185-5p.
Results: Our results indicated that circFGFR4 was significantly overexpressed in TNBC tissues. Upregulated circFGFR4 expression was correlated with decreased CD8⁺ T cell infiltration in tumor tissues and resistance to anti-programmed cell death 1 (PD-1) immunotherapy in TNBC patients and mice bearing TNBC tumors. Forced circFGFR4 expression inhibited CD8⁺ T cell infiltration in tissue sections from TNCB tumor bearing mice. Mechanistically, circFGFR4 competitively sponged miR-185-5p and prevented miR-185-5p from decreasing the levels of C-X-C motif chemokine receptor 4 (CXCR4).
Conclusion: Ultimately, our results indicated that circFGFR4 plays an important role in immune evasion and anti-PD-1 immunotherapy resistance via regulates miR-185-5p/CXCR4 axis in TNBC, thus suggesting that circFGFR4 has significant potential as a biomarker for predicting sensitivity to anti-PD-1 immunotherapy and as an immunotherapeutic target for TNBC.
Keywords: circFGFR4, triple negative breast cancer, TNBC, immune evasion, immunotherapy