CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：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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过继性T细胞疗法（ACT）对少数癌症患者具有治愈效果。使癌细胞对T细胞杀伤敏感化可能扩大这些疗法对更多患者的益处。为此，我们采用三步法来鉴定不利于T细胞免疫的癌症基因。首先，我们分析在T细胞杀伤选择压力下癌症上调的基因转录本。其次，我们利用信号通路激活文库和全基因组功能缺失CRISPR-Cas9筛选，鉴定不利于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，并确定BIRC2、ITGAV、DNPEP、BCL2和ERRα作为潜在的ACT-药物联合候选方案。在此，我们证实BIRC2通过抑制IRF1活性限制抗原呈递和T细胞对肿瘤细胞的识别，并提供证据表明BIRC2抑制联合ACT是提高疗效的有效策略。
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.
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