Establishment of tumor inflammasome clusters with distinct immunogenomic landscape aids immunotherapy.
Establishment of tumor inflammasome clusters with distinct immunogenomic landscape aids immunotherapy.
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建立具有独特免疫基因组景观的肿瘤炎症体簇有助于免疫治疗
作者：
Liang Q;Wu J;Zhao X;Shen S;Zhu C;Liu T;Cui X;Chen L;Wei C;Cheng P;Cheng W;Wu A
炎症体信号传导是影响免疫应答和细胞死亡的反应级联。虽然炎性小体参与肿瘤的发生，但其作为致癌的助推器或肿瘤抑制剂的作用仍然存在争议。因此，重要的是要全面研究炎症体信号转导状态在各种癌症中，以阐明其临床和治疗意义。方法：本研究纳入了来自癌症基因组图谱数据库的33种肿瘤类型的9881例患者。鉴定了五个基因集以逐步分析炎性体信号传导。基于基因集富集的无监督聚类用于样本分类。使用机器学习和体外和体内实验来确认炎性小体分类的含义。结果如下：鉴定了141个炎性小体信号传导相关基因，以构建代表炎性小体信号传导的感测、激活和终止步骤的5个基因集。六个炎性小体簇被稳健地建立，具有不同的分子、生物学、临床和治疗特征。重要的是，发现具有炎性体信号传导激活的簇具有免疫抑制性并且对ICB处理具有抗性。炎性小体抑制逆转了ICB在炎性小体激活的肿瘤中的治疗失败。此外，基于提出的分类和治疗意义，建立了一个开放的网站，为肿瘤患者提供全面的信息，炎症体信号。结论：我们的研究对不同类型肿瘤中的炎性小体信号传导进行了系统的研究。这些发现突出了炎性小体评估在肿瘤分类中的重要性，并为改进相关治疗方案提供了基础。
Inflammasome signaling is a reaction cascade that influences immune response and cell death. Although the inflammasomes participate in tumorigenesis, their role as an oncogenic booster or a tumor suppresser is still controversial. Therefore, it is important to comprehensively investigate the inflammasome signaling status across various cancers to clarify its clinical and therapeutic significance. Methods: A total of 9881 patients across 33 tumor types from The Cancer Genome Atlas database were included in this study. Five gene sets were identified to step-wisely profile inflammasome signaling. Unsupervised clustering was used for sample classification based on gene set enrichment. Machine learning and in vitro and in vivo experiments were used to confirm the implications of inflammasome classification. Results: A hundred and forty-one inflammasome-signaling-related genes were identified to construct five gene sets representing the sensing, activation, and termination steps of the inflammasome signaling. Six inflammasome clusters were robustly established with distinct molecular, biological, clinical, and therapeutic features. Importantly, clusters with inflammasome signaling activation were found to be immunosuppressive and resistant to ICB treatment. Inflammasome inhibition reverted the therapeutic failure of ICB in inflammasome-activated tumors. Moreover, based on the proposed classification and therapeutic implications, an open website was established to provide tumor patients with comprehensive information on inflammasome signaling. Conclusions: Our study conducted a systematical investigation on inflammasome signaling in various tumor types. These findings highlight the importance of inflammasome evaluation in tumor classification and provide a foundation for improving relevant therapeutic regimens.
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DOI：
10.1084/jem.20161707
发表时间：
2017-06-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Daley D;Mani VR;Mohan N;Akkad N;Pandian GSDB;Savadkar S;Lee KB;Torres-Hernandez A;Aykut B;Diskin B;Wang W;Farooq MS;Mahmud AI;Werba G;Morales EJ;Lall S;Wadowski BJ;Rubin AG;Berman ME;Narayanan R;Hundeyin M;Miller G
通讯作者：
Miller G
DOI：
10.1056/nejmoa1402121
发表时间：
2015-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Cancer Genome Atlas Research Network;Brat DJ;Verhaak RG;Aldape KD;Yung WK;Salama SR;Cooper LA;Rheinbay E;Miller CR;Vitucci M;Morozova O;Robertson AG;Noushmehr H;Laird PW;Cherniack AD;Akbani R;Huse JT;Ciriello G;Poisson LM;Barnholtz-Sloan JS;Berger MS;Brennan C;Colen RR;Colman H;Flanders AE;Giannini C;Grifford M;Iavarone A;Jain R;Joseph I;Kim J;Kasaian K;Mikkelsen T;Murray BA;O'Neill BP;Pachter L;Parsons DW;Sougnez C;Sulman EP;Vandenberg SR;Van Meir EG;von Deimling A;Zhang H;Crain D;Lau K;Mallery D;Morris S;Paulauskis J;Penny R;Shelton T;Sherman M;Yena P;Black A;Bowen J;Dicostanzo K;Gastier-Foster J;Leraas KM;Lichtenberg TM;Pierson CR;Ramirez NC;Taylor C;Weaver S;Wise L;Zmuda E;Davidsen T;Demchok JA;Eley G;Ferguson ML;Hutter CM;Mills Shaw KR;Ozenberger BA;Sheth M;Sofia HJ;Tarnuzzer R;Wang Z;Yang L;Zenklusen JC;Ayala B;Baboud J;Chudamani S;Jensen MA;Liu J;Pihl T;Raman R;Wan Y;Wu Y;Ally A;Auman JT;Balasundaram M;Balu S;Baylin SB;Beroukhim R;Bootwalla MS;Bowlby R;Bristow CA;Brooks D;Butterfield Y;Carlsen R;Carter S;Chin L;Chu A;Chuah E;Cibulskis K;Clarke A;Coetzee SG;Dhalla N;Fennell T;Fisher S;Gabriel S;Getz G;Gibbs R;Guin R;Hadjipanayis A;Hayes DN;Hinoue T;Hoadley K;Holt RA;Hoyle AP;Jefferys SR;Jones S;Jones CD;Kucherlapati R;Lai PH;Lander E;Lee S;Lichtenstein L;Ma Y;Maglinte DT;Mahadeshwar HS;Marra MA;Mayo M;Meng S;Meyerson ML;Mieczkowski PA;Moore RA;Mose LE;Mungall AJ;Pantazi A;Parfenov M;Park PJ;Parker JS;Perou CM;Protopopov A;Ren X;Roach J;Sabedot TS;Schein J;Schumacher SE;Seidman JG;Seth S;Shen H;Simons JV;Sipahimalani P;Soloway MG;Song X;Sun H;Tabak B;Tam A;Tan D;Tang J;Thiessen N;Triche T Jr;Van Den Berg DJ;Veluvolu U;Waring S;Weisenberger DJ;Wilkerson MD;Wong T;Wu J;Xi L;Xu AW;Yang L;Zack TI;Zhang J;Aksoy BA;Arachchi H;Benz C;Bernard B;Carlin D;Cho J;DiCara D;Frazer S;Fuller GN;Gao J;Gehlenborg N;Haussler D;Heiman DI;Iype L;Jacobsen A;Ju Z;Katzman S;Kim H;Knijnenburg T;Kreisberg RB;Lawrence MS;Lee W;Leinonen K;Lin P;Ling S;Liu W;Liu Y;Liu Y;Lu Y;Mills G;Ng S;Noble MS;Paull E;Rao A;Reynolds S;Saksena G;Sanborn Z;Sander C;Schultz N;Senbabaoglu Y;Shen R;Shmulevich I;Sinha R;Stuart J;Sumer SO;Sun Y;Tasman N;Taylor BS;Voet D;Weinhold N;Weinstein JN;Yang D;Yoshihara K;Zheng S;Zhang W;Zou L;Abel T;Sadeghi S;Cohen ML;Eschbacher J;Hattab EM;Raghunathan A;Schniederjan MJ;Aziz D;Barnett G;Barrett W;Bigner DD;Boice L;Brewer C;Calatozzolo C;Campos B;Carlotti CG Jr;Chan TA;Cuppini L;Curley E;Cuzzubbo S;Devine K;DiMeco F;Duell R;Elder JB;Fehrenbach A;Finocchiaro G;Friedman W;Fulop J;Gardner J;Hermes B;Herold-Mende C;Jungk C;Kendler A;Lehman NL;Lipp E;Liu O;Mandt R;McGraw M;Mclendon R;McPherson C;Neder L;Nguyen P;Noss A;Nunziata R;Ostrom QT;Palmer C;Perin A;Pollo B;Potapov A;Potapova O;Rathmell WK;Rotin D;Scarpace L;Schilero C;Senecal K;Shimmel K;Shurkhay V;Sifri S;Singh R;Sloan AE;Smolenski K;Staugaitis SM;Steele R;Thorne L;Tirapelli DP;Unterberg A;Vallurupalli M;Wang Y;Warnick R;Williams F;Wolinsky Y;Bell S;Rosenberg M;Stewart C;Huang F;Grimsby JL;Radenbaugh AJ;Zhang J
通讯作者：
Zhang J
影响因子：
11.1
作者：
Chen, Lih-Chyang;Wang, Li-Jie;Tsang, Nang-Ming;Ojcius, David M.;Chen, Chia-Chun;OuYang, Chun-Nan;Hsueh, Chuen;Liang, Ying;Chang, Kai-Ping;Chen, Chiu-Chin;Chang, Yu-Sun
通讯作者：
Chang, Yu-Sun
影响因子：
64.5
作者：
Hoadley KA;Yau C;Wolf DM;Cherniack AD;Tamborero D;Ng S;Leiserson MDM;Niu B;McLellan MD;Uzunangelov V;Zhang J;Kandoth C;Akbani R;Shen H;Omberg L;Chu A;Margolin AA;Van't Veer LJ;Lopez-Bigas N;Laird PW;Raphael BJ;Ding L;Robertson AG;Byers LA;Mills GB;Weinstein JN;Van Waes C;Chen Z;Collisson EA;Cancer Genome Atlas Research Network;Benz CC;Perou CM;Stuart JM
通讯作者：
Stuart JM
影响因子：
10.1
作者：
Dumas, Pierre-Yves;Naudin, Cecile;Pasquet, Jean-Max
通讯作者：
Pasquet, Jean-Max