LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1-TINCR-USP20-PD-L1 axis

Although programmed death-ligand 1 (PD-L1) inhibitors have achieved some therapeutic success in breast cancer, their efficacy is limited by low therapeutic response rates, which is closely related to the immune escape of breast cancer cells. Tissue differentiation inducing non-protein coding RNA (TINCR), a long non-coding RNA, as an oncogenic gene associated with the progression of various malignant tumors, including breast cancer; however, the role of TINCR in tumor immunity, especially in breast cancer, remains unclear. We confirmed that TINCR upregulated PD-L1 expression in vivo and in vitro, and promoted the progression of breast cancer. Next, we revealed that TINCR knockdown can significantly improve the therapeutic effect of PD-L1 inhibitors in breast cancer in vivo. Mechanistically, TINCR recruits DNMT1 to promote the methylation of miR-199a-5p loci and inhibit its transcription. Furthermore, in the cytoplasm, TINCR potentially acts as a molecular sponge of miR-199a-5p and upregulates the stability of USP20 mRNA through a competing endogenous RNA (ceRNA) regulatory mechanism, thus promoting PD-L1 expression by decreasing its ubiquitination level. IFN-gamma stimulation activates STAT1 by phosphorylation, which migrates into the nucleus to promote TINCR transcription. This is the first study to describe the regulatory role of TINCR in breast cancer tumor immunity, broadening the current paradigm of the functional diversity of TINCR in tumor biology. In addition, our study provides new research directions and potential therapeutic targets for PD-L1 inhibitors in breast cancer.

Automated summary

This study found that the long non-coding RNA TINCR upregulates PD-L1 expression and promotes the progression of breast cancer. TINCR regulates the stability of miR-199a-5p and USP20, which affects the expression of PD-L1 and the therapeutic effect of breast cancer. This research broadens the functional diversity of TINCR in tumor biology and provides clues for new research directions and potential therapeutic targets for PD-L1 inhibitors in breast cancer.