Pan-cancer analyses reveal that increased Hedgehog activity correlates with tumor immunosuppression and resistance to immune checkpoint inhibitors.
Pan-cancer analyses reveal that increased Hedgehog activity correlates with tumor immunosuppression and resistance to immune checkpoint inhibitors.
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DOI：
10.1002/cam4.4456
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发表时间：
2022-03
期刊：
影响因子：
4
通讯作者：
Teng L
中科院分区：
文献类型：
--
作者：
Jiang J;Ding Y;Chen Y;Lu J;Chen Y;Wu G;Xu N;Wang H;Teng L
免疫检查点抑制物(ICIS)已在多种癌症类型中显示出许多临床益处，但严重缺乏良好的预测性生物标志物。尽管越来越多的证据表明Hedgehog(HH)信号通路与肿瘤的发生有关，但对其作为生物标记物的潜力的系统研究仍然难以捉摸。我们从癌症基因组图谱和四个已发表的ICI数据库中收集并分析了不同癌症的转录数据和临床结果。通过对HH相关基因进行单样本基因集浓缩分析(SsGSEA)并计算每个肿瘤样本的ssGSEA分数来评估HH活性。我们的研究结果表明，高HH活性的肿瘤表现出多种免疫抑制特征，包括缺乏抗肿瘤反应途径，免疫效应分子下调，免疫抑制细胞和趋化因子丰富，免疫抑制信号激活。值得注意的是，无反应组患者HH活性丰富，总体生存率较差(OS；合并HR=11.50，95%CI=1.02-2.21，P=0.039)。在高程序性细胞死亡配体1(PD-L1)表达亚组中，HH活性高的患者对ICIS的应答率显著降低，OS显著恶化(合并HR=62.89，95%CI=61.53-5.49，P<0.001)。在各种癌症中，HH活性的增加与肿瘤免疫抑制有关。HH活性不仅是ICIS耐药性的预测生物标志物，而且结合PD-L1的表达也可以更好地预测临床结果。这项研究强调，Hedgehog(HH)活性的增加与不同癌症的肿瘤微环境中的多种免疫抑制特征相关。此外，HH活性是转移性癌症患者抵抗免疫检查点抑制剂治疗的预测生物标志物。此外，与单一生物标志物相比，结合程序性细胞死亡配体1的表达能够更好地预测临床结果。
Immune checkpoint inhibitors (ICIs) have shown numerous clinical benefits in multiple cancer types, but good predictive biomarkers are severely lacking. Although increasing evidence has linked Hedgehog (Hh) signaling pathway with tumor development, a systematic investigation for its potential as a biomarker remains elusive. We collected and analyzed the transcriptional data and clinical outcomes of diverse cancers from the Cancer Genome Atlas and four published ICI datasets. Hh activity was estimated by conducting a single‐sample gene‐set enrichment analysis (ssGSEA) for the Hh‐related genes and calculating the ssGSEA score in each tumor sample. Our findings suggest that tumors with high Hh activity displayed multiple immunosuppressive characteristics, including lack of anti‐tumor response pathways, downregulation of immune effectors, enrichment of immunosuppressive cells and chemokines, and activation of immunosuppressive signaling. Notably, patients in the non‐response group had enriched Hh activity and showed worse overall survival (OS; pooled HR = 1.50, 95% CI = 1.02–2.21, p = 0.039). In the subgroup of high programmed cell death ligand 1 (PD‐L1) expression, patients who harbored high Hh activity displayed a dramatically lower response rate to ICIs and a strikingly worse OS (pooled HR = 2.89, 95% CI = 1.53–5.49, p < 0.001). Increased Hh activity correlates with tumor immunosuppression across diverse cancers. Hh activity is not only a predictive biomarker for resistance to ICIs but can also better predict clinical outcomes in combination with PD‐L1 expression. This study highlights that increased Hedgehog (Hh) activity correlated with multiple immunosuppressive characteristics in the tumor microenvironment of diverse cancers. Moreover, Hh activity was a predictive biomarker for resistance to immune checkpoint inhibitor therapy in patients with metastatic cancer. Furthermore, combination with programmed cell death ligand 1 expression was able to better predict clinical outcomes than a single biomarker.
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影响因子：
--
作者：
Chakrabarti, Jayati;Holokai, Loryn;Zavros, Yana
通讯作者：
Zavros, Yana
IV期或复发性非小细胞肺癌中的一线Nivolumab。
DOI：
10.1056/nejmoa1613493
发表时间：
2017-06-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Carbone DP;Reck M;Paz-Ares L;Creelan B;Horn L;Steins M;Felip E;van den Heuvel MM;Ciuleanu TE;Badin F;Ready N;Hiltermann TJN;Nair S;Juergens R;Peters S;Minenza E;Wrangle JM;Rodriguez-Abreu D;Borghaei H;Blumenschein GR Jr;Villaruz LC;Havel L;Krejci J;Corral Jaime J;Chang H;Geese WJ;Bhagavatheeswaran P;Chen AC;Socinski MA;CheckMate 026 Investigators
通讯作者：
CheckMate 026 Investigators
DOI：
10.1126/science.aar3593
发表时间：
2018-10-12
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Cristescu R;Mogg R;Ayers M;Albright A;Murphy E;Yearley J;Sher X;Liu XQ;Lu H;Nebozhyn M;Zhang C;Lunceford JK;Joe A;Cheng J;Webber AL;Ibrahim N;Plimack ER;Ott PA;Seiwert TY;Ribas A;McClanahan TK;Tomassini JE;Loboda A;Kaufman D
通讯作者：
Kaufman D
影响因子：
28.4
作者：
Jabbour, Salma K.;Berman, Abigail T.;Malhotra, Jyoti
通讯作者：
Malhotra, Jyoti
影响因子：
5.5
作者：
Caimano M;Lospinoso Severini L;Loricchio E;Infante P;Di Marcotullio L
通讯作者：
Di Marcotullio L