Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab.
Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab.
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DOI：
10.1186/s40425-018-0404-0
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发表时间：
2018-10-01
影响因子：
10.9
通讯作者：
Taube JM
中科院分区：
文献类型：
--
作者：
Giraldo NA;Nguyen P;Engle EL;Kaunitz GJ;Cottrell TR;Berry S;Green B;Soni A;Cuda JD;Stein JE;Sunshine JC;Succaria F;Xu H;Ogurtsova A;Danilova L;Church CD;Miller NJ;Fling S;Lundgren L;Ramchurren N;Yearley JH;Lipson EJ;Cheever M;Anders RA;Nghiem PT;Topalian SL;Taube JM
我们最近报道了接受pembrolizumab治疗的晚期默克尔细胞癌（MCC）患者的客观缓解率为56%。然而，未发现预测临床应答的生物标志物。通过免疫组织化学/免疫荧光（IHC/IF）对治疗前FFPE肿瘤标本（n = 26）进行CD 8、PD-L1和PD-1染色，并定量阳性细胞的密度和分布，以确定与抗PD-1应答的相关性。使用多重IF检测MCC存档标本的单独队列（n = 16），以鉴定表达PD-1的细胞类型。与无应答者相比，抗PD-1应答患者的肿瘤显示出更高的PD-1+和PD-L1+细胞密度（中位细胞/mm 2，分别为70.7 vs. 6.7，p = 0.03; 855.4 vs. 245.0，p = 0.02）。CD 8+细胞密度与临床应答无显著相关性。位于PD-L1+细胞20 μm范围内的PD-1+细胞的定量显示，PD-1/PD-L1邻近性与临床应答相关（p = 0.03），但CD 8/PD-L1邻近性与临床应答无关。TME中的CD 4+和CD 8+细胞表达相似量的PD-1。虽然TME中PD-L1表达的二项式存在或不存在不足以预测MCC患者对抗PD-1的应答，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之间的地理相互作用与临床应答相关。在TME中表达PD-1的细胞类型包括CD 8 + T细胞、CD 4 + T细胞、T淋巴细胞和CD 20 + B细胞，支持多种细胞类型可在PD-1阻断后增强肿瘤消退的观点。本文的在线版本（10.1186/s40425-018-0404-0）包含补充材料，可供授权用户使用。
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/mm2, 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, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade. The online version of this article (10.1186/s40425-018-0404-0) contains supplementary material, which is available to authorized users.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
11.5
作者：
Giraldo, Nicolas A.;Becht, Etienne;Sautes-Fridman, Catherine
通讯作者：
Sautes-Fridman, Catherine
DOI：
10.1016/s1470-2045(16)30364-3
发表时间：
2016-10
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Kaufman HL;Russell J;Hamid O;Bhatia S;Terheyden P;D'Angelo SP;Shih KC;Lebbé C;Linette GP;Milella M;Brownell I;Lewis KD;Lorch JH;Chin K;Mahnke L;von Heydebreck A;Cuillerot JM;Nghiem P
通讯作者：
Nghiem P
影响因子：
3.5
作者：
Paulson KG;Iyer JG;Simonson WT;Blom A;Thibodeau RM;Schmidt M;Pietromonaco S;Sokil M;Warton EM;Asgari MM;Nghiem P
通讯作者：
Nghiem P
影响因子：
10.1
作者：
Lipson EJ;Vincent JG;Loyo M;Kagohara LT;Luber BS;Wang H;Xu H;Nayar SK;Wang TS;Sidransky D;Anders RA;Topalian SL;Taube JM
通讯作者：
Taube JM