In the last decade, immune
therapies against human
cancers have emerged as a very effective therapeutic strategy in the treatment of various
cancers, some of which are resistant to current
therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further
therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the
transcription factor Yin-Yang 1 (YY1) and the
programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on
tumor cells to the
PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the
tumor cells to both cell killing and inhibition of
tumor progression. Treatment with
nitric oxide (NO) donors has been shown to sensitize many types of
tumors to
chemotherapy,
immunotherapy, and
radiotherapy. Treatment of
cancer cell lines with NO donors has resulted in the inhibition of
cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of
tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-
tumor cytotoxic effector cells or other conventional
therapies will result in a synergistic anticancer activity and
tumor regression.