Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Institute of Inorganic Chemistry, Essen, Germany.
mBio. 2021 Feb 2;12(1):e02121-20. doi: 10.1128/mBio.02121-20.
PD-1-targeted therapies have shown modest antiviral effects in preclinical models of chronic viral infection. Thus, novel therapy protocols are necessary to enhance T cell immunity and viral control to overcome T cell dysfunction and immunosuppression. Here, we demonstrate that nanoparticle-based therapeutic vaccination improved PD-1-targeted therapy during chronic infection with Friend retrovirus (FV). Prevention of inhibitory signals by blocking PD-L1 in combination with therapeutic vaccination with nanoparticles containing the microbial compound CpG and a CD8 T cell Gag epitope peptide synergistically enhanced functional virus-specific CD8 T cell responses and improved viral clearance. We characterized the CD8 T cell populations that were affected by this combination therapy, demonstrating that new effector cells were generated and that exhausted CD8 T cells were reactivated at the same time. While CD8 T cells with high PD-1 (PD-1) expression turned into a large population of granzyme B-expressing CD8 T cells after combination therapy, CXCR5-expressing follicular cytotoxic CD8 T cells also expanded to a high degree. Thus, our study describes a very efficient approach to enhance virus control and may help us to understand the mechanisms of combination immunotherapy reactivating CD8 T cell immunity. A better understanding of CD8 T cell immunity during combination therapy will be important for developing efficient checkpoint therapies against chronic viral infections and cancer. Despite significant efforts, vaccines are not yet available for every infectious pathogen, and the search for a protective approach to prevent the establishment of chronic infections, i.e., with HIV, continues. Immune checkpoint therapies targeting inhibitory receptors, such as PD-1, have shown impressive results against solid tumors. However, immune checkpoint therapies have not yet been licensed to treat chronic viral infections, since a blockade of inhibitory receptors alone provides only limited benefit, as demonstrated in preclinical models of chronic viral infection. Thus, there is a high interest in the development of potent combination immunotherapies. Here, we tested whether the combination of a PD-L1 blockade and therapeutic vaccination with functionalized nanoparticles is a potent therapy during chronic Friend retrovirus infection. We demonstrate that the combination therapy induced a synergistic reinvigoration of the exhausted virus-specific CD8 T cell immunity. Taken together, our results provide further information on how to improve PD-1-targeted therapies during chronic viral infection and cancer.
PD-1 靶向疗法在慢性病毒感染的临床前模型中显示出适度的抗病毒作用。因此，需要新的治疗方案来增强 T 细胞免疫和病毒控制，以克服 T 细胞功能障碍和免疫抑制。在这里，我们证明基于纳米颗粒的治疗性疫苗接种可改善慢性 Friend 逆转录病毒 (FV) 感染中的 PD-1 靶向治疗。通过阻断 PD-L1 与包含微生物化合物 CpG 和 CD8 T 细胞 Gag 表位肽的纳米颗粒的治疗性疫苗接种相结合，抑制信号，协同增强功能性病毒特异性 CD8 T 细胞反应并改善病毒清除。我们对受这种联合治疗影响的 CD8 T 细胞群进行了特征描述，证明同时产生了新的效应细胞并同时激活了耗尽的 CD8 T 细胞。虽然高 PD-1（PD-1）表达的 CD8 T 细胞在联合治疗后变成了大量表达颗粒酶 B 的 CD8 T 细胞，但 CXCR5 表达的滤泡细胞毒性 CD8 T 细胞也高度扩增。因此，我们的研究描述了一种非常有效的增强病毒控制的方法，这可能有助于我们了解联合免疫疗法激活 CD8 T 细胞免疫的机制。更好地了解联合治疗期间的 CD8 T 细胞免疫对于开发针对慢性病毒感染和癌症的有效检查点疗法非常重要。尽管做出了重大努力，但针对每一种传染病病原体，疫苗尚未上市，因此仍在继续寻找预防慢性感染（例如 HIV）建立的保护方法。针对抑制性受体（如 PD-1）的免疫检查点疗法已在实体瘤中显示出令人印象深刻的效果。然而，免疫检查点疗法尚未获准用于治疗慢性病毒感染，因为如慢性病毒感染的临床前模型所示，单独阻断抑制性受体仅提供有限的益处。因此，人们对开发有效的联合免疫疗法非常感兴趣。在这里，我们测试了 PD-L1 阻断和功能性纳米颗粒的治疗性疫苗接种联合是否是慢性 Friend 逆转录病毒感染期间的有效治疗方法。我们证明联合治疗诱导了衰竭的病毒特异性 CD8 T 细胞免疫的协同再激活。总的来说，我们的结果提供了有关如何在慢性病毒感染和癌症期间改善 PD-1 靶向治疗的更多信息。
