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PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells
Erin E. West, … , Kendall A. Smith, Rafi Ahmed
Erin E. West, … , Kendall A. Smith, Rafi Ahmed
Published May 15, 2013
Citation Information: J Clin Invest. 2013;123(6):2604-2615. https://doi.org/10.1172/JCI67008.
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Research Article Immunology

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

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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.

Authors

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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Figure 4

IL-2 therapy affects Tregs during chronic LCMV infection.

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IL-2 therapy affects Tregs during chronic LCMV infection.
C57BL/6 mice w...
C57BL/6 mice were depleted of CD4 T cells and infected with LCMV cl-13. Following day 60 after infection, appropriate groups of mice were treated with PBS/isotype antibody, 200 mg anti–PD-L1 antibody every 3 days for 12 days (5 total treatments), and/or IL-2 (i.p.). IL-2–treated groups were given 1.5 × 104 IU IL-2 (i.p.) twice a day for the duration of the anti–PD-L1 treatment. (A) Representative flow plots showing the frequency of FoxP3+ CD4 T cells in the blood in the middle of treatment (day 8 after start of treatment). (B) Frequency of FoxP3+ CD4 T cells in the blood before (day 0), during (day 8), and after (day 14) treatment. (C) Number of FoxP3+ CD4 T cells in the tissues 2 days after final treatment. (D) Representative histograms showing the expression of CD44, CD25, CD103, and GITR on FoxP3+ CD4 T cells in the spleen after treatment. Numbers represent mean fluorescence intensity. Results are representative of 2 separate experiments, with at least 4 mice per group per experiment. *P < 0.05; **P < 0.01. Error bars indicate the standard deviation of the mean.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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