Immune Marker Profiling and Programmed Death Ligand 1 Expression Across NSCLC Mutations.
Immune Marker Profiling and Programmed Death Ligand 1 Expression Across NSCLC Mutations.
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DOI：
10.1016/j.jtho.2018.09.012
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Rimm DL
中科院分区：
文献类型：
--
作者：
Toki MI;Mani N;Smithy JW;Liu Y;Altan M;Wasserman B;Tuktamyshov R;Schalper K;Syrigos KN;Rimm DL
PD-1/PD-L1轴抑制剂已被证明是有效的，特别是在表达程序性死亡配体1（PD-L1）的肿瘤患者中。它们在表皮生长因子受体（EGFR）激活突变患者中的临床疗效尚不清楚，而KRAS突变似乎与良好的反应相关。我们使用多重定量免疫荧光（QIF）来研究PD-L1表达，并在150多名已知突变状态的非小细胞肺癌（NSCLC）患者中表征肿瘤浸润淋巴细胞（TIL）群体及其活化状态。EGFR突变体中的PD-L1表达显著低于KRAS突变体和EGFR/KRAS野生型（WT）肿瘤。KRAS突变型肿瘤在较高的CD 4+、CD 8+和CD 20 + TIL下炎症更严重。通过TIL活化状态的亚组分析显示，EGFR突变体具有高频率的失活TIL，即使淋巴细胞存在于肿瘤微环境中。相反，在KRAS突变体中，当存在TIL时，它们几乎总是活跃的。此外，我们发现EGFR突变位点在CD 8+表达和TIL活化谱中的差异。最后，在EGFR突变体中，活化的EGFR与PD-L1表达增加相关，但在EGFR WT中不相关，而TIL活化仅在EGFR/KRAS WT中与较高的PD-L1相关。我们的研究结果证明了EGFR突变型肿瘤的独特免疫特征。非活性TIL的高频率可以解释这些患者中免疫治疗应答率低的原因，而PD-L1作为预测性生物标志物可能反映了组成性致癌信号传导而不是免疫信号传导，这与高PD-L1水平和TIL活化相关。
PD-1/PD-L1 axis inhibitors have been proven effective, especially in patients with tumors expressing Programmed Death Ligand 1 (PD-L1). Their clinical efficacy in patients with epidermal growth factor receptor (EGFR) activating mutations is still unclear, while KRAS mutations seem to be associated with good response. We used multiplexed quantitative immunofluorescence (QIF) to investigate PD-L1 expression and to characterize Tumor Infiltrating Lymphocyte (TIL) populations and their activation status in over 150 Non-Small Cell Lung Cancer (NSCLC) patients with known mutation status. PD-L1 expression was significantly lower in EGFR mutant compared to KRAS mutant and EGFR/KRAS Wild Type (WT) tumors. KRAS mutant tumors were more inflamed with higher CD4+, CD8+ and CD20+ TILs. Subgroup analysis by TILs activation status revealed that EGFR mutants had a high frequency of inactive TILs even though lymphocytes were present in the tumor microenvironment. In contrast, in KRAS mutants, when TILs were present, they were almost always active. Additionally, we found differences between EGFR mutation sites in CD8+ expression and TILs activation profile. Finally, activated EGFR correlated with increased PD-L1 expression in EGFR mutants but not in EGFR WT, while TIL activation was associated with higher PD-L1 only in EGFR/KRAS WT. Our findings demonstrate the unique immune profile of EGFR mutant tumors. The high frequency of inactive TILs could explain the low immunotherapy response rates in these patients, while PD-L1 as a predictive biomarker may reflect the constitutive oncogenic signaling rather than immune signaling, which would be associated with high PD-L1 levels and TILs activation.
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影响因子：
45.3
作者：
Eberhard, DA;Johnson, BE;Hillan, KJ
通讯作者：
Hillan, KJ
DOI：
10.1158/1078-0432.ccr-15-3101
发表时间：
2016-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gainor JF;Shaw AT;Sequist LV;Fu X;Azzoli CG;Piotrowska Z;Huynh TG;Zhao L;Fulton L;Schultz KR;Howe E;Farago AF;Sullivan RJ;Stone JR;Digumarthy S;Moran T;Hata AN;Yagi Y;Yeap BY;Engelman JA;Mino-Kenudson M
通讯作者：
Mino-Kenudson M
影响因子：
15.9
作者：
Gu-Trantien, Chunyan;Loi, Sherene;Willard-Gallo, Karen
通讯作者：
Willard-Gallo, Karen
DOI：
10.1056/nejmoa1801946
发表时间：
2018-05-31
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hellmann MD;Ciuleanu TE;Pluzanski A;Lee JS;Otterson GA;Audigier-Valette C;Minenza E;Linardou H;Burgers S;Salman P;Borghaei H;Ramalingam SS;Brahmer J;Reck M;O'Byrne KJ;Geese WJ;Green G;Chang H;Szustakowski J;Bhagavatheeswaran P;Healey D;Fu Y;Nathan F;Paz-Ares L
通讯作者：
Paz-Ares L
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM