Oncogenic mouse double minute 2 homolog (MDM2) is an E3-ubiquitin ligase that facilitates proteasomal degradation of p53. MDM2 amplification occurs in cancer and has been implicated in accelerated tumor growth, known as hyper-progression, following immune-checkpoint therapy. MDM2 amplification also predicts poor response to immune-checkpoint inhibitors. We sought to evaluate the role of MDM2 in T-cell-mediated immune resistance. Ovarian clear cell carcinoma cell lines carrying wild-type p53 with low/high MDM2 expression were investigated in a T-cell co-culture system evaluating T-cell-mediated tumor killing. Targeting of MDM2 was achieved by siRNA transfection or a selective MDM2 inhibitor, AMG-232 and tumor cells were tested in the T-cell co-culture system. AMG-232 activated p53 signaling in cancer cells and relative resistance to AMG-232 was observed in high MDM2-expressing cell lines. Cell lines with high MDM2 expression were more resistant to T cell-mediated tumor killing. Targeting MDM2 by gene-silencing or pharmacological blockade with AMG-232 enhanced T-cell killing of cancer cells. AMG-232 potentiated tumor cell killing by T-cells in combination with anti-PD-1 antibody treatment, regardless of changes in PD-L1 expression. The AMG-232 was not toxic to the T-cells. MDM2 inhibition lowered expression of Interleukin-6, a pro-inflammatory pro-tumorigenic cytokine. Our data support targeting MDM2 in tumors with overexpression or amplification of MDM2 as a precision therapy approach to overcome drug resistance including hyper-progression in the context of immune checkpoint therapy.

中文翻译：

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AMG-232 使高表达 MDM2 的肿瘤细胞对 T 细胞介导的杀伤变得敏感。

致癌小鼠双分钟 2 同源物 (MDM2) 是一种 E3-泛素连接酶，可促进 p53 的蛋白酶体降解。MDM2 扩增发生在癌症中，并与免疫检查点治疗后肿瘤加速生长（称为超进展）有关。MDM2 扩增还预示着对免疫检查点抑制剂的反应不佳。我们试图评估 MDM2 在 T 细胞介导的免疫抵抗中的作用。在 T 细胞共培养系统中研究了携带野生型 p53 并低/高 MDM2 表达的卵巢透明细胞癌细胞系，评估 T 细胞介导的肿瘤杀伤作用。MDM2 的靶向是通过 siRNA 转染或选择性 MDM2 抑制剂 AMG-232 实现的，并且在 T 细胞共培养系统中测试肿瘤细胞。AMG-232 激活癌细胞中的 p53 信号传导，并且在高 MDM2 表达细胞系中观察到对 AMG-232 的相对耐药性。MDM2 高表达的细胞系对 T 细胞介导的肿瘤杀伤具有更强的抵抗力。通过基因沉默或 AMG-232 药理学阻断来靶向 MDM2，可增强 T 细胞对癌细胞的杀伤作用。无论 PD-L1 表达如何变化，AMG-232 与抗 PD-1 抗体治疗相结合，都会增强 T 细胞对肿瘤细胞的杀伤作用。AMG-232 对 T 细胞没有毒性。MDM2 抑制降低了 Interleukin-6（一种促炎促肿瘤细胞因子）的表达。我们的数据支持在 MDM2 过度表达或扩增的肿瘤中靶向 MDM2 作为一种精准治疗方法，以克服耐药性，包括免疫检查点治疗背景下的超进展。