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首页> 外文期刊>The journal of clinical investigation >Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice
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Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice

机译：铂类药物破坏STAT6介导的人类和小鼠抗癌免疫反应的抑制

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Tumor microenvironments feature immune inhibitory mechanisms that prevent T cells from generating effective antitumor immune responses. Therapeutic interventions aimed at disrupting these inhibitory mechanisms have been shown to enhance antitumor immunity, but they lack direct cytotoxic effects. Here, we investigated the effect of cytotoxic cancer chemotherapeutics on immune inhibitory pathways. We observed that exposure to platinum-based chemotherapeutics markedly reduced expression of the T cell inhibitory molecule programmed death receptor-ligand 2 (PD-L2) on both human DCs and human tumor cells. Downregulation of PD-L2 resulted in enhanced antigen-specific proliferation and Th1 cytokine secretion as well as enhanced recognition of tumor cells by T cells. Further analysis revealed that STAT6 controlled downregulation of PD-L2. Consistent with these data, patients with STAT6-expressing head and neck cancer displayed enhanced recurrence-free survival upon treatment with cisplatin-based chemoradiation compared with patients with STAT6-negative tumors, demonstrating the clinical relevance of platinum-induced STAT6 modulation. We therefore conclude that platinum-based anticancer drugs can enhance the immunostimulatory potential of DCs and decrease the immunosuppressive capability of tumor cells. This dual action of platinum compounds may extend their therapeutic application in cancer patients and provides a rationale for their use in combination with immunostimulatory compounds.
机译：肿瘤微环境具有阻止T细胞产生有效抗肿瘤免疫反应的免疫抑制机制。旨在破坏这些抑制机制的治疗性干预措施已被证明可以增强抗肿瘤免疫力，但它们缺乏直接的细胞毒性作用。在这里，我们研究了细胞毒性癌症化学治疗对免疫抑制途径的影响。我们观察到，基于铂的化学疗法的暴露显着降低了人DC和人肿瘤细胞上T细胞抑制分子程序性死亡受体配体2（PD-L2）的表达。 PD-L2的下调导致抗原特异性增殖和Th1细胞因子分泌增强，以及T细胞对肿瘤细胞的识别增强。进一步的分析表明，STAT6控制着PD-L2的下调。与这些数据一致，与STAT6阴性肿瘤患者相比，使用STAT6表达的头颈部癌患者在进行顺铂化学放疗后显示出更高的无复发生存率，证明了铂诱导的STAT6调节的临床意义。因此，我们得出结论，基于铂的抗癌药可以增强DC的免疫刺激潜力，并降低肿瘤细胞的免疫抑制能力。铂化合物的这种双重作用可以扩展其在癌症患者中的治疗应用，并为将其与免疫刺激化合物结合使用提供理论依据。

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