文章：

跨癌种免疫逃逸转录调控因子的鉴定：胆管癌的替代免疫治疗策略

Identification of Transcriptional Regulators of Immune Evasion Across Cancers: An Alternative Immunotherapeutic Strategy for Cholangiocarcinoma

原文发布日期：17 December 2024

DOI: 10.3390/cancers16244197

类型: Article

开放获取: 是

英文摘要：

Background: Cancer immune evasion is a multifaceted process that synchronizes pro-tumoral immune infiltration, immunosuppressive inflammation, and inhibitory immune checkpoint expression (IC). Current immunotherapies combat this issue by reinstating immunosurveillance of tumors; however, it benefits a limited patient population. Thus, a more effective immunotherapeutic strategy is warranted to cater to specific patient populations. This investigation introduces a novel immunotherapeutic strategy via inhibition of master regulators of immune evasion (MR-IE). Methods: Samples of the TCGA Pan-Cancer Atlas transcriptomic data were subset and stratified based on IC and estimated immune cell infiltration. Transcriptomic analysis was conducted to unravel pathways associated with the immune evasion process. Transcription factor enrichment and survival analyses were conducted to identify and rank candidate MR-IEs per cancer type. Results: Inhibition of the top-ranking MR-IE candidate of cholangiocarcinoma (CCA), MYC, modulated the gene and protein expression of PD-L1. Moreover, pro-tumoral inflammatory markers, IFNA21 and CX3CL1, were downregulated, and anti-tumoral cytokines, IL-18 and IL-16, were upregulated. Lastly, MYC inhibition potentiated fourth-generation anti-folate receptor alpha (FRα) CAR-T cell therapy against CCA cells. Conclusions: Cumulatively, this study highlights the promise of MR-IE inhibition as a novel potent immunotherapeutic strategy for the treatment of CCA and offers a candidate list of MR-IEs per cancer type for further validation.

摘要翻译： 

背景：癌症免疫逃逸是一个多方面的过程，涉及促肿瘤免疫浸润、免疫抑制性炎症及抑制性免疫检查点表达（IC）的协同作用。当前免疫疗法通过恢复肿瘤的免疫监视来应对这一问题，但其仅对有限的患者群体有效。因此，需要一种更有效的免疫治疗策略以满足特定患者群体的需求。本研究提出了一种通过抑制免疫逃逸主调控因子（MR-IE）的新型免疫治疗策略。 方法：基于IC及估算的免疫细胞浸润情况，对TCGA泛癌图谱转录组数据样本进行子集划分与分层。通过转录组分析揭示与免疫逃逸过程相关的通路。采用转录因子富集分析与生存分析，按癌症类型识别并排序候选MR-IEs。 结果：抑制胆管癌（CCA）中排名最高的MR-IE候选因子MYC，可调控PD-L1的基因与蛋白表达。此外，促肿瘤炎症标志物IFNA21和CX3CL1表达下调，而抗肿瘤细胞因子IL-18和IL-16表达上调。最后，抑制MYC增强了第四代抗叶酸受体α（FRα）CAR-T细胞疗法对CCA细胞的杀伤作用。 结论：本研究整体表明，抑制MR-IE有望成为治疗CCA的新型高效免疫治疗策略，并提供了按癌症类型分类的MR-IE候选因子列表以供进一步验证。

原文链接：

Identification of Transcriptional Regulators of Immune Evasion Across Cancers: An Alternative Immunotherapeutic Strategy for Cholangiocarcinoma