Department of Thoracic Oncology and CIC1425, Hôpital Bichat-Claude Bernard, Assistance Publique Hôpitaux de Paris, Université Paris-Diderot, Paris, France.
Department of Pathology, Hôpital Bichat-Claude Bernard, AP-HP, Université Paris-Diderot, Paris, France.
Clin Lung Cancer. 2019 Sep;20(5):e564-e575. doi: 10.1016/j.cllc.2019.04.010. Epub 2019 May 13.
Anticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456).
Tumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables.
PD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1-expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1-stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1-positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047).
Although high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.
癌细胞表面程序性死亡配体 1（PD-L1）与程序性细胞死亡 1（PD-1）T 细胞膜蛋白的相互作用，会负向调控抗癌免疫反应。我们试图评估肿瘤样本中 PD-L1 表达在 IFCT-0701 MAPS 随机 3 期试验（NCT00651456）入组患者中的预后作用。
使用 E1L3N 克隆通过免疫组化分析肿瘤样本中 PD-L1 膜染色肿瘤细胞的百分比，并通过包括分层变量的多变量 Cox 模型将数据与生存相关联。
在 448 名患者中的 214 名（47.75%）评估了 PD-L1 染色。上皮样亚型占 83.7%（179/214）。在 214 例恶性胸膜间皮瘤（MPM）样本中，137 例（64.1%）无 PD-L1 染色，77 例（35.9%）为 PD-L1 阳性，其中 50 例（64.9%）肿瘤细胞 PD-L1 表达<50%。肉瘤样/双相亚型比上皮样亚型更常见 PD-L1 阳性（P<0.001）。在 1%或更多 PD-L1 染色肿瘤细胞的患者中，中位总生存期（OS）为 12.3 个月，而其他患者为 22.2 个月（危险比[HR] 1.25；95%置信区间[CI]，0.93-1.67；P=0.14）。在多变量分析中，OS 并未根据 PD-L1 阳性而有所不同（调整后的 HR 1.10；95%CI，0.81-1.49；P=0.55）。以 50%为截断值，PD-L1 阳性患者的中位 OS 为 10.5 个月，而 PD-L1 表达较低的患者为 19.3 个月（HR 1.93；95%CI，1.27-2.93；P=0.002）。在调整后的 Cox 模型中，OS 无显著差异（调整后的 HR 1.20；95%CI，0.74-1.94；P=0.47）。在 179 例上皮样 MPM 患者中，高 PD-L1 染色（≥ 50%的肿瘤细胞）对 OS 有负面影响，尽管不显著，但中位 OS 为 12.3 个月（95%CI，4.3-21.6），而肿瘤 PD-L1 染色<50%细胞的患者中位 OS 为 23 个月（95%CI，18.5-25.2）（P=0.071）。无进展生存期（PFS）差异具有统计学意义，低 PD-L1 染色（<50%细胞）患者的中位 PFS 为 9.9 个月，而高 PD-L1 表达（≥ 50%细胞）患者的中位 PFS 为 6.7 个月（P=0.0047）。
尽管 MAPS 试验中 MPM 患者的高 PD-L1 肿瘤细胞表达与较差的 OS 相关，但在整个队列的多变量分析中，其预后影响消失，而 PD-L1 表达与肉瘤样/双相亚型强烈相关。在上皮样 MPM 患者亚组中，高 PD-L1 肿瘤表达（≥ 50%）对 OS 和 PFS 有负面影响，这种预后影响在多变量 Cox 模型调整后仍具有统计学意义。
