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.

中文翻译：

---

PD-1/LAG-3 协同信号分析揭示了 CBL 泛素连接酶作为关键免疫治疗靶点。


许多癌症患者无法从 PD-L1/PD-1 阻断免疫疗法中受益。 T 细胞中 PD-1 和 LAG-3 的共同上调是通过在 T 细胞中建立高度功能障碍状态而产生耐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 功能障碍相关的共同特征，获得了所有 TCGA 癌症免疫浸润的多组表达谱。发现 PD-1/LAG-3 功能失调特征可调节免疫、代谢、遗传和表观遗传途径，尤其是 TCR 信号体的强化负调节。这些结果在具有组成型活性 PD-1、LAG-3 通路及其组合的 T 细胞系中得到了验证。 PD-1/LAG-3 T 细胞蛋白质组的差异分析显示，参与 E3 泛素化途径的泛素连接酶存在特定富集。 PD-1/LAG-3共同阻断抑制CBL-B表达，而在临床开发中使用双特异性药物也抑制C-CBL表达，从而恢复对PD-L1/PD耐药的肺癌患者的T细胞功能障碍-1封锁。 CBL-B特异性小分子抑制剂与抗PD-1/抗LAG-3免疫疗法的组合在免疫疗法难治性肺癌模型中表现出显着的治疗效果，克服了PD-1/LAG-3介导的耐药性。