PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells
| Autor: | Erin E. West, Ben Youngblood, Wendy G. Tan, Pablo Penaloza-MacMaster, Ata Ur Rasheed, Rafi Ahmed, Sang Jun Ha, Kendall A. Smith, Hyun Tak Jin, Gordon J. Freeman |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Interleukin 2
T cell medicine.medical_treatment Programmed Cell Death 1 Receptor Mice Transgenic CD8-Positive T-Lymphocytes Biology Lymphocyte Activation Lymphocytic choriomeningitis Antiviral Agents T-Lymphocytes Regulatory Antibodies B7-H1 Antigen Interleukin-7 Receptor alpha Subunit Mice medicine Animals Arenaviridae Infections Humans Immunologic Factors Lymphocytic choriomeningitis virus Viremia Interleukin-7 receptor Drug Synergism General Medicine Immunotherapy Viral Load medicine.disease Blockade Mice Inbred C57BL Hyaluronan Receptors medicine.anatomical_structure Chronic Disease Immunology Interleukin-2 Female Viral load CD8 Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 123:2604-2615 |
| ISSN: | 0021-9738 |
| Popis: | The inhibitory receptor programmed cell death 1 (PD-1) plays a major role in functional exhaustion of T cells during chronic infections and cancer, and recent clinical data suggest that blockade of the PD-1 pathway is an effective immunotherapy in treating certain cancers. Thus, it is important to define combinatorial approaches that increase the efficacy of PD-1 blockade. To address this issue, we examined the effect of IL-2 and PD-1 ligand 1 (PD-L1) blockade in the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. We found that low-dose IL-2 administration alone enhanced CD8+ T cell responses in chronically infected mice. IL-2 treatment also decreased inhibitory receptor levels on virus-specific CD8+ T cells and increased expression of CD127 and CD44, resulting in a phenotype resembling that of memory T cells. Surprisingly, IL-2 therapy had only a minimal effect on reducing viral load. However, combining IL-2 treatment with blockade of the PD-1 inhibitory pathway had striking synergistic effects in enhancing virus-specific CD8+ T cell responses and decreasing viral load. Interestingly, this reduction in viral load occurred despite increased numbers of Tregs. These results suggest that combined IL-2 therapy and PD-L1 blockade merits consideration as a regimen for treating human chronic infections and cancer. |
| Databáze: | OpenAIRE |
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