PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells

Erin E. West, Hyun Tak Jin, Ata Ur Rasheed, Pablo Penaloza-MacMaster, Sang Jun Ha, Wendy G. Tan, Ben Youngblood, Gordon J. Freeman, Kendall A. Smith, Rafi Ahmed

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141 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2604-2615
Number of pages12
JournalJournal of Clinical Investigation
Volume123
Issue number6
DOIs
Publication statusPublished - 2013 Jun 3

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    West, E. E., Jin, H. T., Rasheed, A. U., Penaloza-MacMaster, P., Ha, S. J., Tan, W. G., Youngblood, B., Freeman, G. J., Smith, K. A., & Ahmed, R. (2013). PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. Journal of Clinical Investigation, 123(6), 2604-2615. https://doi.org/10.1172/JCI67008