YY1 regulates cancer cell immune resistance by modulating PD-L1 expression

Abstract

Recent advances in the treatment of various cancers have resulted in the adaptation of several novel immunotherapeutic strategies. Notably, the recent intervention through immune checkpoint inhibitors has resulted in significant clinical responses and prolongation of survival in patients with several therapy-resistant cancers (melanoma, lung, bladder, etc.). This intervention was mediated by various antibodies directed against inhibitory receptors expressed on cytotoxic T-cells or against corresponding ligands expressed on tumor cells and other cells in the tumor microenvironment (TME). However, the clinical responses were only observed in a subset of the treated patients; it was not clear why the remaining patients did not respond to checkpoint inhibitor therapies. One hypothesis stated that the levels of PD-L1 expression correlated with poor clinical responses to cell-mediated anti-tumor immunotherapy. Hence, exploring the underlying mechanisms that regulate PD-L1 expression on tumor cells is one approach to target such mechanisms to reduce PD-L1 expression and, therefore, sensitize the resistant tumor cells to respond to PD-1/PD-L1 antibody treatments. Various investigations revealed that the overexpression of the transcription factor Yin Yang 1 (YY1) in most cancers is involved in the regulation of tumor cells' resistance to cell-mediated immunotherapies. We, therefore, hypothesized that the role of YY1 in cancer immune resistance may be correlated with PD-L1 overexpression on cancer cells. This hypothesis was investigated and analysis of the reported literature revealed that several signaling crosstalk pathways exist between the regulations of both YY1 and PD-L1 expressions. Such pathways include p53, miR34a, STAT3, NF-kB, PI3K/AKT/mTOR, c-Myc, and COX-2. Noteworthy, many clinical and pre-clinical drugs have been utilized to target these above pathways in various cancers independent of their roles in the regulation of PD-L1 expression. Therefore, the direct inhibition of YY1 and/or the use of the above targeted drugs in combination with checkpoint inhibitors should result in enhancing the cell-mediated anti-tumor cell response and also reverse the resistance observed with the use of checkpoint inhibitors alone.

Keywords: Crosstalks; PD-L1; Signaling; Therapy; YY1.