Systematic identification and targeting of master regulator checkpoints (MRC) governing tumor microenvironment-mediated immune evasion.

IF 10.3 1区 医学 Q1 IMMUNOLOGY
Pasquale Laise, Gideon Bosker, Mariana Babor, Xiaoyun Sun, Stuart Andrews, Lorenzo Tomassoni, Andrea Califano, Mariano Alvarez
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引用次数: 0

Abstract

Abrogating the immunoevasive role of the tumor immune microenvironment (TIME) represents a critical yet still elusive challenge in cancer treatment. Progress in this area has been hampered by both technological limitations and incomplete understanding of TIME-dependent immunoevasion mechanisms. We hypothesize that the immune-evasive role of TIME subpopulations-including regulatory T cells, cancer-associated fibroblasts, and tumor-associated macrophages-is critically mediated by hyperconnected Master Regulator Checkpoint (MRC) modules whose aberrant activity, as induced by paracrine signals, can be abrogated or modulated either genetically or pharmacologically. MRCs are primarily composed of transcription and co-transcription factors, acting downstream of surface receptors and signal transduction cascades to control the transcriptional identity and, ultimately, the phenotype of individual TIME subpopulations. Pharmacological inhibition of subpopulation-specific MRC proteins can thus help reprogram the TIME and potentially abrogate or modulate its immunosuppressive state. This paradigm shift, away from single ligand/receptor targeting, is supported by recent algorithmic, experimental, and clinical advances allowing systematic identification of MRCs and their pharmacological modulators using systems immunology-based approaches. Refocusing the deployment of existing tools and experimental methods that have proven successful in tumor cell contexts to identify and validate MRC-targeting agents capable of remodeling the immunosuppressive cell states of the tumor microenvironment can potentially pave the road to novel combination therapy synergizing with immune checkpoint inhibitors.

控制肿瘤微环境介导的免疫逃避的主调节检查点(MRC)的系统识别和靶向。
消除肿瘤免疫微环境(TIME)的免疫逃避作用是癌症治疗中一个关键但仍难以捉摸的挑战。由于技术限制和对时间依赖性免疫逃避机制的不完全了解,这一领域的进展受到阻碍。我们假设TIME亚群(包括调节性T细胞、癌症相关成纤维细胞和肿瘤相关巨噬细胞)的免疫逃避作用是由超连接的主调节检查点(MRC)模块介导的,这些模块的异常活动是由旁分泌信号诱导的,可以通过遗传或药理学方式被取消或调节。MRCs主要由转录因子和共转录因子组成,作用于表面受体的下游和信号转导级联,以控制转录身份,并最终控制单个TIME亚群的表型。因此,亚群特异性MRC蛋白的药理学抑制可以帮助重新编程TIME,并可能消除或调节其免疫抑制状态。这种从单一配体/受体靶向的范式转变,得到了最近的算法、实验和临床进展的支持,这些进展允许使用基于系统免疫的方法系统地识别MRCs及其药理学调节剂。重新聚焦已在肿瘤细胞环境中证明成功的现有工具和实验方法的部署,以识别和验证能够重塑肿瘤微环境的免疫抑制细胞状态的mrc靶向药物,可能为与免疫检查点抑制剂协同的新型联合治疗铺平道路。
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来源期刊
Journal for Immunotherapy of Cancer
Journal for Immunotherapy of Cancer Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
17.70
自引率
4.60%
发文量
522
审稿时长
18 weeks
期刊介绍: The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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