XIST and TSIX: Novel Cancer Immune Biomarkers in PD-L1-Overexpressing Breast Cancer Patients

Abstract

Escaping antitumor immunity is a hallmark in cancer progression. Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor responsible for the maintenance of immune tolerance; PD-1 ligand (PD-L1) is overexpressed in tumor cells, simplifying their escape from the immune system through T-cell function suppression. Notwithstanding that cancer antigen (CA)125, carcinoembryonic antigen (CEA), CA15-3, and alpha-fetoprotein (AFP) are among conventional breast cancer diagnostic biomarkers, their lack of sensitivity and specificity resides among their major limitations. Furthermore, human epidermal growth factor receptor (HER)2 and interleukin (IL)-6—demonstrated as breast cancer immune biomarkers—still possess limitations, for instance, technical detection problems and stability problems, which necessitate the discovery of novel, stable non-invasive cancer immune biomarkers. XIST and TSIX are two long non-coding (lnc)RNAs possessing a role in X chromosome inactivation (XCI) as well as in breast cancer (BC). In the present study, they were investigated as stable non-invasive breast cancer immune biomarkers. The study demonstrated that PD-L1 was overexpressed in the different molecular subtypes of breast cancer patients as well as in MDA-MB-231 cells. Furthermore, lncRNAs XIST and TSIX were markedly increased in the tissues, lymph nodes, and different body fluids of breast cancer patients compared to controls. In addition, XIST and TSIX were differentially expressed in subtypes of BC patients, and their levels were correlated to PD-L1 expression level. In conclusion, this correlative study has shed light on the role of both lncRNAs XIST and TSIX as potential non-invasive BC immune biomarkers reflecting the evaded immune system of the patient and overcoming the instability problem of common BC biomarkers.