A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells
| Autor: | Matthias Epple, Gennadiy Zelinskyy, Torben Knuschke, Astrid M. Westendorf, Philine Steinbach, Ulf Dittmer, Sebastian Kollenda, Christina Wenzek, Jan Buer |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
retroviruses
medicine.medical_treatment Medizin CD8-Positive T-Lymphocytes Lymphocyte Activation Mice 0302 clinical medicine checkpoint inhibition Cytotoxic T cell Immune Checkpoint Inhibitors Cells Cultured T cell exhaustion 0303 health sciences biology Vaccination QR1-502 Friend murine leukemia virus medicine.anatomical_structure 030220 oncology & carcinogenesis chronic retrovirus infection Female immunotherapy chronic viral infection Research Article Receptors CXCR5 Combination therapy T cell T cells Chemie Microbiology 03 medical and health sciences Virology exhaustion medicine Animals 030304 developmental biology business.industry therapeutic vaccination Immunotherapy Therapeutics and Prevention Immune checkpoint Mice Inbred C57BL Chronic infection Granzyme Immunology biology.protein nanoparticles business CD8 Retroviridae Infections |
| Zdroj: | mBio, Vol 12, Iss 1 (2021) mBio |
| ISSN: | 2150-7511 2161-2129 |
| Popis: | 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. 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-1hi) 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. |
| Databáze: | OpenAIRE |
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