DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma.
DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma.
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DOI：
10.1136/jitc-2021-003420
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发表时间：
2022-03
影响因子：
10.9
通讯作者：
Fuereder T
中科院分区：
文献类型：
--
作者：
Starzer AM;Heller G;Tomasich E;Melchardt T;Feldmann K;Hatziioannou T;Traint S;Minichsdorfer C;Schwarz-Nemec U;Nackenhorst M;Müllauer L;Preusser M;Berghoff AS;Fuereder T
针对头颈部鳞状细胞癌（HNSCC）患者，迫切需要用于预测抗程序性细胞死亡1（PD-1）免疫检查点抑制剂（ICI）应答的生物标志物，以实现个性化治疗方法。我们研究了用抗PD-1 ICI治疗的HNSCC患者的炎症参数和DNA甲基化谱的预测潜力。我们在两个独立的中心确定了在进展至含铂化疗后复发或转移情况下接受抗PD-1 ICI治疗的HNSCC患者。我们通过Infinium MethylationEPIC微阵列分析了这些患者肿瘤标本中>850.000个CpG位点的DNA甲基化谱，肿瘤微环境中的免疫细胞密度，（CD 8、CD 3、CD 45 RO、叉头框P3（FOXP 3）、CD 68）、通过免疫组织化学的PD-1和程序性细胞死亡配体1（PD-L1）表达以及血液炎症标志物（血小板与淋巴细胞比率、白细胞与淋巴细胞比率、单核细胞与淋巴细胞比率、嗜中性粒细胞与淋巴细胞比率）。DNA甲基化谱和免疫学标志物与抗PD-1 ICI的放射学反应在生物信息学和统计学上相关。纳入了37例HNSCC患者（中位年龄62岁;范围49-83岁; 8例（21.6%）女性，29例（78.4%）男性）（中心1 N=26，70.3%;中心2 N=11，29.7%）。既往全身治疗的中位次数为1次（范围1-4次）。37例患者中有5例（13.5%）实现了ICI的客观缓解。中位无进展生存期和中位总生存期分别为3.7个月（范围0-22.9）和9.0个月（范围0-38.8）。微阵列分析揭示了甲基化特征，包括低甲基化和高甲基化，这是对ICI反应的预测，包括参与癌症相关分子途径的几个基因。应答者和非应答者之间过度表达的差异甲基化基因与“Axon指导”、“Hippo信号传导”、“癌症通路”和“MAPK信号传导”相关。PD-L1表达与缓解存在统计学显著相关性（p=0.0498）。我们的研究结果表明，肿瘤DNA甲基化谱可能有助于预测HNSCC患者对ICI的反应。
Biomarkers for response prediction to anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) are urgently needed for a personalized therapy approach. We investigated the predictive potential of inflammatory parameters and DNA methylation profiling in patients with HNSCC treated with anti-PD-1 ICI. We identified patients with HNSCC that were treated with anti-PD-1 ICI therapy in the recurrent or metastatic setting after progression to platinum-based chemotherapy in two independent centers. We analyzed DNA methylation profiles of >850.000 CpG sites in tumor specimens of these patients by Infinium MethylationEPIC microarrays, immune cell density in the tumor microenvironment (CD8, CD3, CD45RO, forkhead box P3 (FOXP3), CD68), PD-1 and programmed cell death ligand 1 (PD-L1) expression by immunohistochemistry, and blood inflammation markers (platelet-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio). DNA methylation profiles and immunological markers were bioinformatically and statistically correlated with radiological response to anti-PD-1 ICI. 37 patients with HNSCC (median age of 62 years; range 49–83; 8 (21.6%) women, 29 (78.4%) men) were included (Center 1 N=26, 70.3%; Center 2 N=11, 29.7%). Median number of prior systemic therapies was 1 (range 1–4). Five out of 37 (13.5%) patients achieved an objective response to ICI. Median progression-free survival and median overall survival times were 3.7 months (range 0–22.9) and 9.0 months (range 0–38.8), respectively. Microarray analyses revealed a methylation signature including both hypomethylation and hypermethylation which was predictive for response to ICI and included several genes involved in cancer-related molecular pathways. Over-represented differentially methylated genes between responders and non-responders were associated with ‘Axon guidance’, ‘Hippo signaling’, ‘Pathways in cancer’ and ‘MAPK signaling’. A statistically significant correlation of PD-L1 expression and response was present (p=0.0498). Our findings suggest that tumor DNA methylation profiling may be useful to predict response to ICI in patients with HNSCC.
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影响因子：
64.8
作者：
Capper D;Jones DTW;Sill M;Hovestadt V;Schrimpf D;Sturm D;Koelsche C;Sahm F;Chavez L;Reuss DE;Kratz A;Wefers AK;Huang K;Pajtler KW;Schweizer L;Stichel D;Olar A;Engel NW;Lindenberg K;Harter PN;Braczynski AK;Plate KH;Dohmen H;Garvalov BK;Coras R;Hölsken A;Hewer E;Bewerunge-Hudler M;Schick M;Fischer R;Beschorner R;Schittenhelm J;Staszewski O;Wani K;Varlet P;Pages M;Temming P;Lohmann D;Selt F;Witt H;Milde T;Witt O;Aronica E;Giangaspero F;Rushing E;Scheurlen W;Geisenberger C;Rodriguez FJ;Becker A;Preusser M;Haberler C;Bjerkvig R;Cryan J;Farrell M;Deckert M;Hench J;Frank S;Serrano J;Kannan K;Tsirigos A;Brück W;Hofer S;Brehmer S;Seiz-Rosenhagen M;Hänggi D;Hans V;Rozsnoki S;Hansford JR;Kohlhof P;Kristensen BW;Lechner M;Lopes B;Mawrin C;Ketter R;Kulozik A;Khatib Z;Heppner F;Koch A;Jouvet A;Keohane C;Mühleisen H;Mueller W;Pohl U;Prinz M;Benner A;Zapatka M;Gottardo NG;Driever PH;Kramm CM;Müller HL;Rutkowski S;von Hoff K;Frühwald MC;Gnekow A;Fleischhack G;Tippelt S;Calaminus G;Monoranu CM;Perry A;Jones C;Jacques TS;Radlwimmer B;Gessi M;Pietsch T;Schramm J;Schackert G;Westphal M;Reifenberger G;Wesseling P;Weller M;Collins VP;Blümcke I;Bendszus M;Debus J;Huang A;Jabado N;Northcott PA;Paulus W;Gajjar A;Robinson GW;Taylor MD;Jaunmuktane Z;Ryzhova M;Platten M;Unterberg A;Wick W;Karajannis MA;Mittelbronn M;Acker T;Hartmann C;Aldape K;Schüller U;Buslei R;Lichter P;Kool M;Herold-Mende C;Ellison DW;Hasselblatt M;Snuderl M;Brandner S;Korshunov A;von Deimling A;Pfister SM
通讯作者：
Pfister SM
影响因子：
12.3
作者：
Mueller, Fabian;Scherer, Michael;Bock, Christoph
通讯作者：
Bock, Christoph
影响因子：
7.4
作者：
Seremet T;Koch A;Jansen Y;Schreuer M;Wilgenhof S;Del Marmol V;Liènard D;Thielemans K;Schats K;Kockx M;Van Criekinge W;Coulie PG;De Meyer T;van Baren N;Neyns B
通讯作者：
Neyns B
DOI：
10.1056/nejmoa1510665
发表时间：
2015-11-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Motzer RJ;Escudier B;McDermott DF;George S;Hammers HJ;Srinivas S;Tykodi SS;Sosman JA;Procopio G;Plimack ER;Castellano D;Choueiri TK;Gurney H;Donskov F;Bono P;Wagstaff J;Gauler TC;Ueda T;Tomita Y;Schutz FA;Kollmannsberger C;Larkin J;Ravaud A;Simon JS;Xu LA;Waxman IM;Sharma P;CheckMate 025 Investigators
通讯作者：
CheckMate 025 Investigators
影响因子：
158.5
作者：
Schmid, P.;Adams, S.;Emens, L. A.
通讯作者：
Emens, L. A.