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ATM/NEMO signaling modulates the expression of PD-L1 following docetaxel chemotherapy in prostate cancer
BACKGROUND: The efficacy of docetaxel-based chemotherapy is limited by the development of drug resistance. Recent studies demonstrated the efficacy of anti-programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immunotherapies in metastatic prostate cancer. The ataxia telangiectasia mutati...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296819/ https://www.ncbi.nlm.nih.gov/pubmed/34301812 http://dx.doi.org/10.1136/jitc-2020-001758 |
Sumario: | BACKGROUND: The efficacy of docetaxel-based chemotherapy is limited by the development of drug resistance. Recent studies demonstrated the efficacy of anti-programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immunotherapies in metastatic prostate cancer. The ataxia telangiectasia mutation (ATM) protein plays a crucial role in maintaining genome stability and function of mitosis. Here, we aimed to determine whether PD-1/PD-L1 signaling contributes to the resistance to DTX and to elucidate the mechanism underlying DTX-induced PD-L1 expression. METHODS: In this retrospective study, PD-L1 expression was analyzed in 33 tumor tissue samples from prostate cancer patients. Prostate cell lines were used to perform functional assays and examine underlying mechanisms in vitro. A fully mouse prostate cancer model and a humanized chimeric mouse bearing human prostate tumors and peripheral blood mononuclear cells were used for in vivo assays. RESULTS: We have shown that DTX, a chemotherapeutic drug which causing microtubule interference, could significantly induce the expression of PD-L1 in prostate cancer cells. This effect is blocked by the inhibition of ATM, suggesting that it plays an essential role in PD-L1 expression upregulated by DTX. Mechanistic studies have shown that ATM activity in cancer cells enhances the stability of the NF-κB essential modulator (NEMO), which leading to an increase in the NF-κB activity and PD-L1 expression. Using the mouse model, it was further demonstrated that a combination of ATM and NEMO inhibitors along with DTX augmented the antitumor efficacy of chemotherapy, which are comparable to that of PD-L1 antibody. CONCLUSIONS: Our findings have revealed that a previously unrecognized ATM-NEMO signaling which induced by DTX is capable of suppressing tumor immunity by activating the expression of PD-L1, suggesting that the ATM-NEMO-NF-κB axis can be exploited to restore the immune balance and overcome cancer resistance triggered by DTX. Graphic Abstract: supplementary file 1 |
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