Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers
Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers
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DOI：
10.1073/pnas.1800695115
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发表时间：
2018-10-02
影响因子：
11.1
通讯作者：
Lu, Xin
中科院分区：
文献类型：
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作者：
Feng, Shan;Cheng, Xi;Lu, Xin
肿瘤微环境中的有效免疫抑制机制有助于侵袭性人类癌症对免疫检查点阻断（ICB）疗法的抵抗。髓源性抑制细胞（MDSC）诱导T细胞耐受的主要机制之一是通过分泌活性氮物质（RNS），其硝酸化参与T细胞功能的蛋白质中的酪氨酸残基。然而，到目前为止，很少有硝化蛋白质已被确定。在这里，使用前列腺癌的转基因小鼠模型和肺癌的同基因细胞系模型，我们应用了基于3-硝基酪氨酸的化学衍生的硝基蛋白质组学方法，并确定淋巴细胞特异性蛋白酪氨酸激酶（LCK），T细胞受体信号级联中的起始酪氨酸激酶，被MDSC在Tyr 394处硝化。LCK硝化抑制T细胞活化，导致白细胞介素2（IL 2）产生和增殖减少。在具有缺陷性内源性LCK的人T细胞中，野生型而非硝化的LCK拯救IL 2产生。在前列腺特异性缺失Pten、p53和Smad 4的去势抵抗性前列腺癌（CRPC）小鼠模型中，CRPC对由抗程序性细胞死亡1（PD 1）和抗细胞毒性T淋巴细胞相关蛋白4（CTLA 4）抗体组成的ICB治疗具有抗性。然而，我们表明，ICB与RNS中和剂联合使用时，具有较强的抗CRPC疗效。总之，这些数据确定了MDSC诱导的蛋白质硝化导致T细胞失活的一种先前未知的机制，并阐明了ICB与RNS还原剂联合治疗CRPC的临床路径假设。
Potent immunosuppressive mechanisms within the tumor microenvironment contribute to the resistance of aggressive human cancers to immune checkpoint blockade (ICB) therapy. One of the main mechanisms for myeloid-derived suppressor cells (MDSCs) to induce T cell tolerance is through secretion of reactive nitrogen species (RNS), which nitrates tyrosine residues in proteins involved in T cell function. However, so far very few nitrated proteins have been identified. Here, using a transgenic mouse model of prostate cancer and a syngeneic cell line model of lung cancer, we applied a nitroproteomic approach based on chemical derivation of 3-nitrotyrosine and identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs. LCK nitration inhibits T cell activation, leading to reduced interleukin 2 (IL2) production and proliferation. In human T cells with defective endogenous LCK, wild type, but not nitrated LCK, rescues IL2 production. In the mouse model of castration-resistant prostate cancer (CRPC) by prostate-specific deletion of Pten, p53, and Smad4, CRPC is resistant to an ICB therapy composed of antiprogrammed cell death 1 (PD1) and anticytotoxic-T lymphocyte-associated protein 4 (CTLA4) antibodies. However, we showed that ICB elicits strong anti-CRPC efficacy when combined with an RNS neutralizing agent. Together, these data identify a previously unknown mechanism of T cell inactivation by MDSC-induced protein nitration and illuminate a clinical path hypothesis for combining ICB with RNSreducing agents in the treatment of CRPC.