PDF(Pubmed)
Abstract：
PD-1 blockade therapy has revolutionized melanoma treatment, but still not all patients benefit and pre-treatment identification of those patients is difficult. Increased expression of inflammatory markers such as interleukin (IL)-6 in blood of patients correlates with poor treatment response. We set out to study the effect of inflammatory cytokines on PD-1 blockade in vitro. For this, we studied the effect of IL-6 and type I interferon (IFN) in vitro on human T cells in a mixed leukocyte reaction (MLR) in the absence or presence of PD-1 blockade. While IL-6 reduced IFN-γ secretion by T cells in both the presence and absence of PD-1 blockade, IFN-α specifically reduced the IFN-γ secretion only in the presence of PD-1 blockade. IFN-α reduced T cell proliferation independent of PD-1 blockade and reduced the percentage of cells producing IFN-γ only in the presence of PD-1 blockade. Next we determined the type I IFN score in a cohort of 22 melanoma patients treated with nivolumab. In this cohort, we did not find a correlation between clinical response and type I IFN score, nor between clinical response and IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade. We conclude that IFN-α reduces the effectiveness of PD-1 blockade in vitro, but that in this cohort, type I IFN score in vivo, nor IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade correlated to decreased therapy responses in patients.
摘要：
PD-1阻断疗法彻底改变了黑色素瘤治疗，但仍然不是所有的患者都受益，并且这些患者的治疗前识别是困难的。患者血液中炎性标志物如白细胞介素(IL)-6的表达增加与不良治疗反应相关。我们着手体外研究炎性细胞因子对PD-1阻断的影响。为此，我们研究了在不存在或存在PD-1阻断的情况下,IL-6和I型干扰素(IFN)在混合白细胞反应(MLR)中体外对人T细胞的影响.虽然IL-6在存在和不存在PD-1阻断的情况下都会降低T细胞的IFN-γ分泌，IFN-α仅在PD-1阻断的存在下特异性减少IFN-γ分泌。IFN-α独立于PD-1阻断降低T细胞增殖,并且仅在PD-1阻断的存在下降低产生IFN-γ的细胞的百分比。接下来，我们确定了一组22例用纳武单抗治疗的黑色素瘤患者的I型IFN评分。在这个队列中，我们没有发现临床反应和I型IFN评分之间的相关性，在存在PD-1阻断的情况下，MLR中的临床反应和体外IFN-γ分泌之间也没有。我们得出的结论是，IFN-α在体外降低了PD-1阻断的有效性，但是在这个群体中，体内I型IFN评分，在存在PD-1阻断的情况下，MLR中的体外IFN-γ分泌也与患者的治疗反应降低相关。
