Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
Clin Cancer Res. 2021 Mar 1;27(5):1371-1380. doi: 10.1158/1078-0432.CCR-20-3084. Epub 2020 Nov 20.
We sought to validate levels of CD8 tumor-infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (IF biomarker; Pignon and colleagues, 2019) and to investigate human endogenous retroviruses (hERV) as predictors of response to anti-PD-1 in a randomized trial of nivolumab (nivo) versus everolimus (evero) in patients with metastatic clear cell renal cell carcinoma (mccRCC; CheckMate-025).
Tumor tissues (nivo: = 116, evero: = 107) were analyzed by multiparametric immunofluorescence (IF) and qRT-PCR. Genomic/transcriptomic analyses were performed in a subset of samples. Clinical endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and durable response rate (DRR, defined as complete response or partial response with a PFS ≥ 12 months).
In the nivo (but not evero) arm, patients with high-IF biomarker density (24/116, 20.7%) had higher ORR (45.8% vs. 19.6%, = 0.01) and DRR (33.3% vs. 14.1%, = 0.03) and longer median PFS (9.6 vs. 3.7 months, = 0.03) than patients with low-IF biomarker. By RNA sequencing, several inflammatory pathways ( < 0.1) and immune-related gene signature scores ( < 0.05) were enriched in the high-IF biomarker group. When combined with the IF biomarker, tumor cell (TC) PD-L1 expression (≥1%) further separated clinical outcomes in the nivo arm. expression was associated with increased DRR and longer PFS in nivo-treated patients.
High levels of CD8 TIC expressing PD-1 but not TIM-3 and LAG-3 and expression predicted response to nivo (but not to evero) in patients with mccRCC. Combination of the IF biomarker with TC PD-L1 improved its predictive value, confirming our previous findings.
我们旨在验证表达 PD-1 但不表达 TIM-3 和 LAG-3 的 CD8 肿瘤浸润细胞（TIC）水平（IF 生物标志物；Pignon 等人，2019 年），并研究人类内源性逆转录病毒（hERV）作为纳武单抗（nivo）与依维莫司（evero）在转移性透明细胞肾细胞癌（mccRCC；CheckMate-025）患者中随机试验中抗 PD-1 反应预测因子。
通过多参数免疫荧光（IF）和 qRT-PCR 分析 nivo（nivo：=116，evero：=107）肿瘤组织。对部分样本进行基因组/转录组分析。临床终点包括客观缓解率（ORR）、无进展生存期（PFS）、总生存期（OS）和持久缓解率（DRR，定义为完全缓解或部分缓解且 PFS≥12 个月）。
在 nivo（而非 evero）组中，高 IF 生物标志物密度（24/116，20.7%）的患者具有更高的 ORR（45.8% vs. 19.6%，=0.01）和 DRR（33.3% vs. 14.1%，=0.03）以及更长的中位 PFS（9.6 个月 vs. 3.7 个月，=0.03）比低 IF 生物标志物患者。通过 RNA 测序，在高 IF 生物标志物组中，几种炎症途径（<0.1）和免疫相关基因特征评分（<0.05）富集。当与 IF 生物标志物结合时，肿瘤细胞（TC）PD-L1 表达（≥1%）进一步分离了 nivo 组的临床结局。在 nivo 治疗的患者中，表达与更高的 DRR 和更长的 PFS 相关。
表达 PD-1 但不表达 TIM-3 和 LAG-3 的高水平 CD8 TIC 和 表达预测了 mccRCC 患者对 nivo（而非 evero）的反应。IF 生物标志物与 TC PD-L1 的结合提高了其预测价值，证实了我们之前的发现。
