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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 5

IL-2 therapy modulates exhausted antiviral CD8 T cells.

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IL-2 therapy modulates exhausted antiviral CD8 T cells.
2 × 103 Thy1.1+ ...
2 × 103 Thy1.1+ DbGP33 LCMV-specific CD8 T cells (P14 transgenic) were transferred i.v. into C57/BL6 mice (Thy1.2+) that were subsequently infected with LCMV cl-13, and beginning on day 23 to 27 after infection, the mice were treated with 1.5 × 104 IU IL-2 (i.p.) every 24 hours for 6 days. On the seventh day, the mice were either treated with PBS or 1.5 × 104 IU IL-2 and mice were sacrificed 30 minutes after IL-2 treatment. Splenocytes were removed and stained with Thy1.1, CD8, and phospho-STAT-5 antibodies. (A) Experimental set up. (B) Frequency of P14 T cells in the blood (gated on CD8) and (C) number in the spleen before and after 6 days of IL-2 treatment. (D) Percentage of P14 T cells in the spleen that are phospho-STAT-5 positive. (E) Representative FACS plots showing phospho-STAT-5 staining of P14 T cells. (F) Representative histogram showing phospho-STAT-5 staining of P14 T cells. Numbers on graph indicate MFI. (G) Representative histograms of CD25, CD122, and CD132 expression on P14 T cells in the blood before and after IL-2 treatment. Results are representative of 2 independent experiments, with at least 4 mice per group. *P < 0.05. 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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