Laboratory of Cancer Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.
Department of Internal Medicine, Division of Oncology, University Hospital Basel, Basel, Switzerland.
Clin Cancer Res. 2019 May 15;25(10):3026-3034. doi: 10.1158/1078-0432.CCR-18-3041. Epub 2019 Feb 14.
PD-(L)1-blocking antibodies have clinical activity in metastatic non-small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade. Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways.
Peripheral blood mononuclear cells were collected from 35 patients with NSCLC receiving nivolumab monotherapy. Cellular changes, cytokine levels, gene expression, and polymorphisms were compared between responders and nonresponders to treatment. Findings were confirmed in additional cohorts of patients with NSCLC receiving immune checkpoint blockade.
We identified a genetic variant of a killer cell immunoglobulin-like receptor (KIR) that is associated with primary resistance to PD-1 blockade in patients with NSCLC. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients, the progression-free survival was significantly associated with presence of the allele (HR, 1.72; 95% confidence interval, 1.10-2.68; = 0.017). No relationship was seen in cohorts of patients with NSCLC who did not receive immunotherapy. Cellular assays from patients before and during PD-1 blockade showed that resistance may be due to NK-cell dysfunction.
We identified an association of the allelic variant with response to PD-1-targeted immunotherapy in patients with NSCLC. This finding links NK cells with response to PD-1 therapy. Although the findings are interesting, a larger analysis in a randomized trial will be needed to confirm KIRs as predictive markers for response to PD-1-targeted immunotherapy.
PD-(L)1 阻断抗体在转移性非小细胞肺癌（NSCLC）中具有临床活性，并介导持久的肿瘤缓解。然而，大多数患者对 PD-(L)1 阻断有耐药性。了解原发性耐药的机制可能有助于预测临床反应，并确定新的靶向途径。
从 35 名接受纳武单抗单药治疗的 NSCLC 患者中收集外周血单核细胞。比较治疗反应者和无反应者之间的细胞变化、细胞因子水平、基因表达和多态性。在接受免疫检查点阻断的 NSCLC 患者的其他队列中验证了这些发现。
我们鉴定了一种杀伤细胞免疫球蛋白样受体（KIR）的遗传变异，该变异与 NSCLC 患者对 PD-1 阻断的原发性耐药相关。这种关联可以在 NSCLC 患者的独立队列中得到证实。在对 135 名患者的汇总队列进行多变量分析中，无进展生存期与 等位基因的存在显著相关（HR，1.72；95%置信区间，1.10-2.68； = 0.017）。在未接受免疫治疗的 NSCLC 患者队列中未观察到这种关系。患者在 PD-1 阻断前后的细胞测定表明，耐药可能是由于 NK 细胞功能障碍所致。
我们鉴定了 NSCLC 患者对 PD-1 靶向免疫治疗的反应与 等位基因变异的关联。这一发现将 NK 细胞与对 PD-1 治疗的反应联系起来。尽管这些发现很有趣，但需要在随机试验中进行更大规模的分析，以确认 KIRs 作为 PD-1 靶向免疫治疗反应的预测标志物。
