PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets.

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EMBO Molecular Medicine Pub Date : 2024-08-01 Epub Date: 2024-07-19 DOI:10.1038/s44321-024-00098-y
Luisa Chocarro, Ester Blanco, Leticia Fernandez-Rubio, Maider Garnica, Miren Zuazo, Maria Jesus Garcia, Ana Bocanegra, Miriam Echaide, Colette Johnston, Carolyn J Edwards, James Legg, Andrew J Pierce, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Ruth Vera, Karina Ausin, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Grazyna Kochan, David Escors
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Abstract

Many cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance.

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PD-1/LAG-3协同信号分析发现CBL泛素连接酶是关键的免疫疗法靶点。
许多癌症患者无法从 PD-L1/PD-1 阻断免疫疗法中获益。T细胞中的PD-1和LAG-3共调控通过在T细胞中建立高度功能失调状态而成为抗药性的主要机制之一。为了确定人类癌症和T细胞中与PD-1/LAG-3功能失调相关的共同特征,我们获得了所有TCGA癌症免疫浸润的多组学表达谱。研究发现,PD-1/LAG-3功能失调特征可调控免疫、代谢、遗传和表观遗传途径,尤其是加强了对TCR信号组的负调控。这些结果在具有组成性活性 PD-1、LAG-3 途径及其组合的 T 细胞系中得到了验证。对 PD-1/LAG-3 T 细胞蛋白质组的差异分析表明,参与 E3 泛素化途径的泛素连接酶特别丰富。PD-1/LAG-3联合阻断抑制了CBL-B的表达,而使用临床开发中的一种双特异性药物也抑制了C-CBL的表达,从而恢复了对PD-L1/PD-1阻断耐药的肺癌患者的T细胞功能障碍。CBL-B特异性小分子抑制剂与抗PD-1/抗LAG-3免疫疗法相结合,在免疫疗法难治的肺癌模型中显示出显著疗效,克服了PD-1/LAG-3介导的耐药性。
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来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
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