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.
Highlights
Breast cancer (BC) is the most commonly diagnosed cancer in females and has the highest fatality rate among other cancer types [1], competing with heart disease in being the leading cause of death worldwide [2]
The results verified the variation in PD-L1 expression across diverse BC patients’ molecular subtypes as both luminal B, and triple-negative BC (TNBC) demonstrated significant upregulation of PD-L1 (p = 0.0044 and p < 0.0001, respectively), in contrast to luminal A who displayed a significant downregulation of programmed cell death-ligand 1 (PDL1) (p = 0.0181), in addition to a non-significant expression of PD-L1 in HER2/luminal B and HER2/neu compared to controls
LncRNA XIST showed significant upregulation in HER2/neu subtype (p = 0.0344), it demonstrated a non-significant change in expression in HER2/luminal B and TNBC subtypes compared to healthy breast tissues (Figure 2), in addition to significant upregulation of lncRNA TSIX in HER2/luminal B and TNBC subtypes (p < 0.0001, and p < 0.001, respectively), it demonstrated a non-significant change in expression in HER2/neu subtype compared to healthy breast tissues (Figure 3)
Summary
Breast cancer (BC) is the most commonly diagnosed cancer in females and has the highest fatality rate among other cancer types [1], competing with heart disease in being the leading cause of death worldwide [2]. PD-L1 and its receptor programmed cell death protein 1 (PD-1) are immune checkpoint regulators promoting selftolerance by protecting the body from the excessive T-cell activity, inflammation, and autoimmunity [8] This is maintained through PD-1 (expressed on T cells)/PD-L1 (expressed mainly in nonlymphoid organs) ligand binding leading to T-cell suppression [9]. PD-L1 expression [18], high tumor mutation load [19], HER2 [20], and interleukin (IL)-6 [21] were successful illustrations of tumor and BC immune biomarkers, their technical detection problems [22] and instability in extended cryopreservation blood samples [23] have urged the discovery of novel stable immune biomarkers, the long non-coding (lnc)RNAs. To date, lncRNAs execute pivotal roles as cancer biomarkers as they are highly sensitive, specific, and stable in different body fluids, especially if they were circulating enclosed within apoptotic bodies or exosomes [24]. It was reported in Shi et al [25] that the lncRNAs successfully resisted ribonuclease enzyme as they were effectively detected in different body fluids where ribonuclease enzymes were present in rich quantities
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