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

Hays, Emily; Bonavida, Benjamin

doi:10.1016/j.drup.2019.04.001

Cited by 106 publications

(84 citation statements)

References 266 publications

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“…NO also induces RKIP, PTEN, Fas, and DR5 expressions, leading to the sensitization of tumor cells to FasL, TRAIL, and chemotherapeutic-induced apoptosis [56]. Because YY1 inhibition by NO leads to the sensitization of cancer cells to both chemotherapy and immunotherapy [145], and YY1 mediates the expression of PD-L1 in tumor cells [35], NO may play a role in sensitizing tumor cells to anti-PD1/anti-PD-L1 therapy. The treatment of tumor cells with a NO donor resulted in the inhibition of YY1 DNA-binding activities by S-nitrosylating the cysteine residues involved in DNA binding [146].…”

Section: Nitric Oxide In Overcoming Immune and Chemo Resistancementioning

confidence: 99%

“…Other factors have been shown to be involved in acquiring resistance to immunotherapies, such as the drug efflux transporter and other membrane drug transporters that shuttle drugs across cell membranes, protecting the cell from the accumulation of toxic drugs [34]. The transcription factor, YY1, has also been shown to regulate immune resistance by modulating the expression of PD-L1 in cancer cells through several crosstalk pathways [35]. The inhibition of YY1 sensitizes tumor cells to apoptosis [36] and may be a potential therapeutic target for overcoming immune resistance.…”

Section: Introductionmentioning

confidence: 99%

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Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

Hays

Bonavida

2019

Antioxidants

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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.

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Section: Nitric Oxide In Overcoming Immune and Chemo Resistancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

Hays

Bonavida

2019

Antioxidants

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“…Signaling through PD-1 in T cells subverts TCR signal transduction and CD80/CD86-CD28 costimulation, inhibiting cytokine release and causing cell cycle arrest [77] . While the exact mechanisms of how PD-L1 is upregulated in cancer cells remain unclear, previous evidence suggests that the transcription factor YY1 [78] , phosphatases Src homology region 2 domain-containing phosphatase-1 and 2 (SHP 1/2) [77] , and cyclin-dependent kinases 4 and 6 (CDK 4/6) [79] all regulate PD-L1 expression in some way. PD-L1 expression in various cancers, such as lung cancer, colorectal cancer, and melanoma, has been correlated with cancer progression and poor survival [80] and dampened signs of CTL activity [75] .…”

Section: Immune Checkpoint Ligandsmentioning

confidence: 99%

Cell-mediated immune resistance in cancer

Wang¹,

Hays²,

Rama³

et al. 2019

CDR

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The genetic and epigenetic aberrations that underlie immune resistance lead to tumors that are refractory to clinically established and experimental immunotherapies, including monoclonal antibodies and T cell-based therapies. From various forms of cytotoxic T cells to small molecule inhibitors that revamp the tumor microenvironment, these therapies have demonstrated notable responses in cancer models and a resistant subset of cancer patients, used both alone and in combination. However, even current approaches, such as those targeting checkpoint molecules, tumor ligands, and involving gene-related therapies, present a challenge in non-responding patients. In this perspective, we discuss the most common mechanisms of immune resistance, including tumor heterogeneity, tumor ligand and major histocompatibility complex modulation, anti-apoptotic pathways, checkpoint inhibitory ligands, immunosuppressive cells and factors in the tumor microenvironment, and activation-induced cell death. In addition, we discuss the strategies designed to circumvent these resistance pathways to showcase the potential of emerging technologies in battling the rise of resistance.

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“…When P53 is inhibited, it can no longer induce miR‐34a transcription, and miR‐34a can no longer degrade PD‐L1. Moreover, YY1 can also be through the cytokines IL‐6, IL‐17, TGF‐β, and IFN, the signaling pathway PTEN/PI3K/AKT/mTOR (Mammalian target of rapamycin), c‐Myc, COX‐2, etc, regulates PD‐L1 117 . However, not all patients with positive PD‐L1 expression responded to PD‐1/PD‐L1 monoclonal antibody.…”

Section: Influence Of Tumor Microenvironment On Clinical Treatment Rementioning

confidence: 99%

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

Wang

2020

Cancer Medicine

116

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Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD‐1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD‐L1 (programmed cell death‐ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD‐1/PD‐L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti‐PD‐1 monoclonal antibody Nivolumab, Pembrolizumab, and anti‐PD‐L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long‐term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD‐1 or PD‐L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti‐PD‐1/PD‐L1 drug resistance in tumors, the potential biomarkers for predicting PD‐1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long‐term clinical efficacy.

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

Cited by 106 publications

References 266 publications

Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

Cell-mediated immune resistance in cancer

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

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