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

Research output: Contribution to journalArticle

130 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

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Interleukin-2
Ligands
T-Lymphocytes
Viral Load
Cell Death
CD274 Antigen
Programmed Cell Death 1 Receptor
Therapeutics
Viruses
Lymphocytic choriomeningitis virus
Neoplasms
Virus Diseases
Infection
Immunotherapy
Phenotype

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

West, E. E., Jin, H. T., Rasheed, A. U., Penaloza-MacMaster, P., Ha, S. J., Tan, W. G., ... 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
West, Erin E. ; Jin, Hyun Tak ; Rasheed, Ata Ur ; Penaloza-MacMaster, Pablo ; Ha, Sang Jun ; Tan, Wendy G. ; Youngblood, Ben ; Freeman, Gordon J. ; Smith, Kendall A. ; Ahmed, Rafi. / PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 6. pp. 2604-2615.
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West, EE, Jin, HT, Rasheed, AU, Penaloza-MacMaster, P, Ha, SJ, Tan, WG, Youngblood, B, Freeman, GJ, Smith, KA & Ahmed, R 2013, 'PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells', Journal of Clinical Investigation, vol. 123, no. 6, pp. 2604-2615. https://doi.org/10.1172/JCI67008

PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. / West, Erin E.; Jin, Hyun Tak; Rasheed, Ata Ur; Penaloza-MacMaster, Pablo; Ha, Sang Jun; Tan, Wendy G.; Youngblood, Ben; Freeman, Gordon J.; Smith, Kendall A.; Ahmed, Rafi.

In: Journal of Clinical Investigation, Vol. 123, No. 6, 03.06.2013, p. 2604-2615.

Research output: Contribution to journalArticle

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