Although PD-1-targeted therapies are now licensed to treat human cancers, not all patients respond equally to ICTs. However, these therapies show clinical limits that are not fully understood. Immune checkpoint therapies (ICTs), i.e., those targeting inhibitory receptor programmed cell death-1 (PD-1) signaling, restore the cytotoxic function of CD8 + T cells and enhance their expansion by blocking inhibitory signals ( 3). Thus, there is a strong interest in the development of potent strategies to reinforce CD8 + T cell immunity to control or eradicate chronic infections. 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.ĬD8 + T cell dysfunction is associated with chronic viral infection ( 1, 2).
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. While CD8 + T cells with high PD-1 (PD-1 hi) 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. 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. 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. Here, we demonstrate that nanoparticle-based therapeutic vaccination improved PD-1-targeted therapy during chronic infection with Friend retrovirus (FV). Thus, novel therapy protocols are necessary to enhance T cell immunity and viral control to overcome T cell dysfunction and immunosuppression. PD-1-targeted therapies have shown modest antiviral effects in preclinical models of chronic viral infection.
0 kommentar(er)
