Department of Medical Oncology, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
J Clin Invest. 2011 Aug;121(8):3100-8. doi: 10.1172/JCI43656. Epub 2011 Jul 18.
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.
肿瘤微环境具有免疫抑制机制，可防止 T 细胞产生有效的抗肿瘤免疫反应。已证实针对这些抑制机制的治疗干预可增强抗肿瘤免疫，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疗药物对免疫抑制途径的影响。我们观察到，暴露于基于铂的化疗药物会显着降低人 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 PD-L2 的下调。与这些数据一致的是，与 STAT6 阴性肿瘤患者相比，表达 STAT6 的头颈部癌症患者在接受顺铂为基础的放化疗后表现出增强的无复发生存期，这证明了铂诱导的 STAT6 调节的临床相关性。因此，我们得出结论，基于铂的抗癌药物可以增强 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能会扩展它们在癌症患者中的治疗应用，并为它们与免疫刺激化合物联合使用提供了依据。
