Cancer genes disfavoring T cell immunity identified via integrated systems approach.
Cancer genes disfavoring T cell immunity identified via integrated systems approach.
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DOI：
10.1016/j.celrep.2022.111153
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发表时间：
2022-08-02
期刊：
影响因子：
8.8
通讯作者：
Restifo, Nicholas P.
中科院分区：
文献类型：
--
作者：
Kishton, Rigel J.;Patel, Shashank J.;Decker, Amy E.;Vodnala, Suman K.;Cam, Maggie;Yamamoto, Tori N.;Patel, Yogin;Sukumar, Madhusudhanan;Yu, Zhiya;Ji, Michelle;Henning, Amanda N.;Gurusamy, Devikala;Palmer, Douglas C.;Stefanescu, Roxana A.;Girvin, Andrew T.;Lo, Winifred;Pasetto, Anna;Malekzadeh, Parisa;Deniger, Drew C.;Wood, Kris C.;Sanjana, Neville E.;Restifo, Nicholas P.
免疫性T细胞疗法（ACT）已经治愈了有限数量的癌症患者。癌细胞对T细胞杀伤的敏感性可能会扩大这些疗法对更多患者的益处。为此，我们使用三步方法来识别不利于T细胞免疫的癌症基因。首先，我们分析了在T细胞杀伤的选择压力下癌症上调的基因转录本。其次，我们使用信号通路激活文库和全基因组功能丧失CRISPR-Cas9筛选来识别不利于T细胞杀伤的潜在肿瘤基因靶点和通路。最后，我们实施药理学扰动筛选以验证这些靶点，并将BIRC 2、ITGAV、DNPEP、BCL 2和ERRα确定为潜在的ACT-药物组合候选物。在这里，我们确定BIRC 2通过抑制IRF 1活性限制肿瘤细胞的抗原呈递和T细胞识别，并提供证据表明BIRC 2抑制与ACT联合是提高疗效的有效策略。Kishton等人使用系统方法来鉴定保护癌症免受T细胞介导的杀伤的肿瘤基因和信号通路。用组合方法靶向这些肿瘤防御增加了肿瘤的T细胞消除，并且可能是提高免疫疗法临床疗效的策略。
Adoptive T cell therapies (ACT) have been curative for a limited number of cancer patients. The sensitization of cancer cells to T cell killing may expand the benefit of these therapies for more patients. To this end, we use a three-step approach to identify cancer genes that disfavor T cell immunity. First, we profile gene transcripts upregulated by cancer under selection pressure from T cell killing. Second, we identify potential tumor gene targets and pathways that disfavor T cell killing using signaling pathway activation libraries and genome-wide loss-of-function CRISPR-Cas9 screens. Finally, we implement pharmacological perturbation screens to validate these targets and identify BIRC2, ITGAV, DNPEP, BCL2, and ERRα as potential ACT-drug combination candidates. Here, we establish that BIRC2 limits antigen presentation and T cell recognition of tumor cells by suppressing IRF1 activity and provide evidence that BIRC2 inhibition in combination with ACT is an effective strategy to increase efficacy. Kishton et al. use systems approaches to identify tumor genes and signaling pathways that protect cancer from T cell-mediated killing. Targeting these tumor defenses with combination approaches increases T cell elimination of tumors and may be a strategy to improve the clinical efficacy of immunotherapy.
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影响因子：
64.8
作者：
Manguso RT;Pope HW;Zimmer MD;Brown FD;Yates KB;Miller BC;Collins NB;Bi K;LaFleur MW;Juneja VR;Weiss SA;Lo J;Fisher DE;Miao D;Van Allen E;Root DE;Sharpe AH;Doench JG;Haining WN
通讯作者：
Haining WN
影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
DOI：
10.1056/nejmoa1407222
发表时间：
2014-10-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Maude SL;Frey N;Shaw PA;Aplenc R;Barrett DM;Bunin NJ;Chew A;Gonzalez VE;Zheng Z;Lacey SF;Mahnke YD;Melenhorst JJ;Rheingold SR;Shen A;Teachey DT;Levine BL;June CH;Porter DL;Grupp SA
通讯作者：
Grupp SA
影响因子：
10.1
作者：
Lo, Winifred;Parkhurst, Maria;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
4.4
作者：
Robbins, Paul F.;Li, Yong F.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.