通过基于PD-1的免疫开关受体模块化递送共刺激信号改善了乙型肝炎病毒特异性工程T细胞的功能
Modular delivery of co-stimulatory signals through a PD-1-based immunoswitch receptor improves the functionality of Hepatitis B Virus-specific engineered T cells.
摘要(中文译文)
在慢性乙型肝炎病毒感染（cHBV）中，T细胞应答发生偏斜。这阻碍了HBV感染肝细胞的清除，促进肝细胞癌的发生，并限制了T细胞疗法的疗效。为在过继性T细胞疗法中拮抗免疫检查点PD-1/PD-L1相互作用，我们开发了基于PD-1的免疫开关受体，可将PD-L1结合转化为共刺激信号。我们设计了将PD-1胞外域与胞内CD28、4-1BB或OX40信号域连接的免疫开关受体，并在HBV特异性嵌合抗原受体（CAR）T细胞和T细胞受体工程化T细胞中表达。通过抗原和PD-L1依赖性共培养、转录因子报告系统及HBV携带小鼠模型评估T细胞活性。第二代S-CAR的功能并未因叠加额外共刺激信号域而改善，反而导致功能失调的活化状态，而非叠加获益。相比之下，通过基于PD-1的免疫开关受体模块化递送共刺激信号，增强了工程化T细胞的抗原敏感性、功能性和细胞毒性。反式提供的PD-L1足以通过免疫开关受体共刺激支持工程化T细胞的靶向功能。PD-1_4-1BB在诱导持续NF-κB信号和减少耗竭相关通路方面表现更优。PD-1_4-1BB改善了T细胞持久性并减少了TOX上调。基于PD-1的免疫开关受体提供了一种模块化策略，在肝脏的耐受环境中增强工程化T细胞针对HBV抗原表达细胞的应答。这种配体驱动的方法能够精确调节共刺激信号，为增强慢性感染和癌症中的过继性T细胞疗法提供了一个多功能平台。
Abstract
In chronic hepatitis B virus infection (cHBV), T-cell responses are skewed. This prevents the elimination of HBV-infected hepatocytes, contributes to hepatocellular carcinoma development, and limits the efficacy of T-cell therapies. To counteract the immune checkpoint PD-1/PD-L1-interaction in adoptive T-cell therapy, we developed PD-1-based immunoswitch receptors that convert PD-L1 engagement into co-stimulation. We designed immunoswitch receptors linking a PD-1 ectodomain to intracellular CD28, 4-1BB, or OX40 signaling domains and expressed them in HBV-specific chimeric antigen receptor (CAR)- and T-cell receptor-engineered T cells. T-cell activity was assessed in antigen- and PD-L1-dependent co-cultures, transcription factor reporter systems, and an HBV carrier mouse model. Second-generation S-CAR functionality was not improved by signal stacking of additional co-stimulatory domains, resulting in a dysfunctional activation state rather than an additive benefit. In contrast, modular delivery of co-stimulation through PD-1-based immunoswitch receptors enhanced antigen sensitivity, functionality, and cytotoxicity of engineered T cells. PD-L1 supplied in trans was sufficient to support on-target functionality of engineered T cells by immunoswitch receptor co-stimulation. PD-1_4-1BB proved superior at inducing sustained NF-κB signaling and reducing exhaustion-associated pathways. , PD-1_4-1BB improved T-cell persistence and decreased TOX upregulation. PD-1-based immunoswitch receptors offer a modular strategy to strengthen engineered T-cell responses against HBV antigen-expressing cells in the liver's tolerizing environment. This ligand-driven approach enables precise tuning of co-stimulation, generating a versatile platform for enhancing adoptive T-cell therapies in chronic infections and cancer.
如何引用
AMA
Luis Felipe Olguín-Contreras, Johanna Heep, Lisa Schiller, Eva Loffredo-Verde, Marvin M Festag, Kai Metzger, et al. Modular delivery of co-stimulatory signals through a PD-1-based immunoswitch receptor improves the functionality of Hepatitis B Virus-specific engineered T cells.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1821414.
APA
Luis Felipe Olguín-Contreras, Johanna Heep, Lisa Schiller, Eva Loffredo-Verde, Marvin M Festag, Kai Metzger, et al (2026). Modular delivery of co-stimulatory signals through a PD-1-based immunoswitch receptor improves the functionality of Hepatitis B Virus-specific engineered T cells.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1821414
GB/T 7714
Luis Felipe Olguín-Contreras, Johanna Heep, Lisa Schiller, Eva Loffredo-Verde, Marvin M Festag, Kai Metzger, et al. Modular delivery of co-stimulatory signals through a PD-1-based immunoswitch receptor improves the functionality of Hepatitis B Virus-specific engineered T cells.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1821414.
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