Isothiocyanates attenuate immune checkpoint blockage therapy in gastric cancer via induction of PD-L1 expression.
Isothiocyanates attenuate immune checkpoint blockage therapy in gastric cancer via induction of PD-L1 expression.
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DOI：
10.1016/j.jnutbio.2022.109226
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发表时间：
2022-11
期刊：
影响因子：
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通讯作者：
Qi Zhang;Wanshuang Cao;Chenying Yang;Lixia Hong;Shan-shan Geng;Hong-yu Han;Cai-yun Zhong
中科院分区：
文献类型：
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作者：
Qi Zhang;Wanshuang Cao;Chenying Yang;Lixia Hong;Shan-shan Geng;Hong-yu Han;Cai-yun Zhong
PD-1/PD-L1免疫检查点阻断疗法在包括胃癌在内的多种癌症的治疗中显示出革命性的疗效。异硫氰酸酯在肿瘤细胞抑制和免疫调节中起重要作用。然而，异硫氰酸酯对免疫检查点抑制剂在胃癌中的作用知之甚少。研究了三种主要的异硫氰酸酯（萝卜硫素、异硫氰酸苯乙酯和异硫氰酸二苯甲基酯）对胃癌细胞生长和PD-L1表达的影响。采用异硫氰酸酯和抗PD-L1单克隆抗体建立同系小鼠模型，评价其抗肿瘤作用。检测PD-L1表达、淋巴细胞比例及血清细胞因子水平，探讨其机制。我们发现异硫氰酸酯显著诱导PD-L1表达，这与TAp 63 α上调有关。我们进一步揭示了TAp 63 α通过转录激活促进PD-L1。异硫氰酸酯联合抗PD-L1治疗可降低胃癌细胞对抗PD-L1药物的敏感性。此外，体内研究表明，异硫氰酸酯对抗PD-L1抗体的干扰作用与荷瘤小鼠宿主中PD-L1表达和浸润T淋巴细胞减少有关。我们的研究结果提供了新的见解，因为异硫氰酸酯可能会干扰免疫治疗在胃癌中的成功应用。
The PD-1/PD-L1 immune checkpoint blockade therapy has shown revolutionary efficacy in the treatment of multiple cancers including gastric cancer. Isothiocyanates play important roles in cancer cell suppression and immunomodulation. However, the effects of isothiocyanates on immune checkpoint inhibitors are poorly understood in gastric cancer. The influence of three major isothiocyanates (sulforaphane, phenylethyl isothiocyanate, and benzhydryl isothiocyanate) on gastric cancer cell growth and PD-L1 expression was investigated. Syngeneic mouse models were administered by isothiocyanates and anti-PD-L1 monoclonal antibody, and the anti-tumor effects were assessed. The expression of PD-L1, proportion of lymphocytes and serum cytokine levels were detected to explore the underlying mechanisms. We found that PD-L1 expression was significantly induced by isothiocyanates which was associated with TAp63α up-regulation. We further revealed that TAp63α promoted PD-L1 through transcriptional activation. Combination treatment of isothiocyanates and anti-PD-L1 therapy weakened the sensitivity of gastric cancer cells to anti-PD-L1 drug. Moreover,in vivostudies illustrated that the interference effects of isothiocyanates on anti-PD-L1 antibody were related to PD-L1 expression and decreased infiltrating T lymphocytes in tumor bearing mouse hosts. Our findings provide novel insights as isothiocyanates could interfere with the successful application of immunotherapy in gastric cancer.