Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Immunother Cancer. 2018 Oct 1;6(1):99. doi: 10.1186/s40425-018-0404-0.
We recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. However, a biomarker predicting clinical response was not identified.
Pretreatment FFPE tumor specimens (n = 26) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry/immunofluorescence (IHC/IF), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response. Multiplex IF was used to test a separate cohort of MCC archival specimens (n = 16), to identify cell types expressing PD-1.
Tumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders (median cells/mm, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively). There was no significant association of CD8+ cell density with clinical response. Quantification of PD-1+ cells located within 20 μm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response (p = 0.03), but CD8/PD-L1 proximity was not. CD4+ and CD8+ cells in the TME expressed similar amounts of PD-1.
While the binomial presence or absence of PD-L1 expression in the TME was not sufficient to predict response to anti-PD-1 in patients with MCC, we show that quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations correlate with clinical response. Cell types expressing PD-1 in the TME include CD8+ T-cells, CD4+ T-cells, T, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.
我们最近报道了接受派姆单抗治疗的晚期 Merkel 细胞癌（MCC）患者的客观缓解率为 56%。然而，尚未确定预测临床反应的生物标志物。
对 26 例预处理 FFPE 肿瘤标本进行 CD8、PD-L1 和 PD-1 的免疫组化/免疫荧光染色（IHC/IF），并对阳性细胞的密度和分布进行定量，以确定与抗 PD-1 反应的相关性。使用多重 IF 检测 MCC 存档标本的另一个队列（n=16），以鉴定表达 PD-1 的细胞类型。
与无反应者相比，对 PD-1 有反应的患者的肿瘤中 PD-1+和 PD-L1+细胞的密度更高（中位数细胞/mm，70.7 与 6.7，p=0.03；855.4 与 245.0，p=0.02）。CD8+细胞密度与临床反应无显著相关性。定量分析 PD-1+细胞位于 PD-L1+细胞 20μm 以内的情况表明，PD-1/PD-L1 接近与临床反应相关（p=0.03），但 CD8/PD-L1 接近则不然。TME 中的 CD4+和 CD8+细胞表达的 PD-1 量相似。
虽然 TME 中 PD-L1 表达的二元存在与否不足以预测 MCC 患者对抗 PD-1 的反应，但我们表明，PD-1+和 PD-L1+细胞密度的定量评估以及这两种细胞群体之间的地理相互作用与临床反应相关。TME 中表达 PD-1 的细胞类型包括 CD8+T 细胞、CD4+T 细胞、T 细胞和 CD20+B 细胞，这支持了多种细胞类型可能在 PD-1 阻断后促进肿瘤消退的观点。
