Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia

Qing Zhou, Meghan E. Munger, Rachelle G. Veenstra, Brenda J. Weigel, Mitsuomi Hirashima, David H. Munn, William J Murphy, Miyuki Azuma, Ana C. Anderson, Vijay K. Kuchroo, Bruce R. Blazar

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326 Scopus citations

Abstract

Tumor-associated immune suppression can lead to defective T cell-mediated antitumor immunity. Here, we identified a unique phenotype of exhausted T cells in mice with advanced acute myelogenous leukemia (AML). This phenotype is characterized by the coexpression of Tim-3 and PD-1 on CD8+ T cells in the liver, the major first site of AML metastases. PD-1 and Tim-3 coexpression increased during AML progression. PD-1+Tim-3+ CD8+ T cells were deficient in their ability to produce IFN-γ, TNF-α, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, up-regulated Tim-3 during AML progression and such Tim-3+PD-1- KO CD8+ T cells had reduced cytokine production. Galectin-9 KO mice were more resistant to AML, which was associated with reduced T-regulatory cell accumulation and a modest induction of PD-1 and Tim-3 expression on CD8+ T cells. Whereas blocking the PD-1/ PDL1 or Tim-3/galectin-9 pathway alone was insufficient to rescue mice from AML lethality, an additive effect was seen in reducing - albeit not eliminating - both tumor burden and lethality when both pathways were blocked. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8+ T-cell exhaustion in patients with hematologic malignancies such as advanced AML.

Original languageEnglish (US)
Pages (from-to)4501-4510
Number of pages10
JournalBlood
Volume117
Issue number17
DOIs
StatePublished - Apr 28 2011

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Zhou, Q., Munger, M. E., Veenstra, R. G., Weigel, B. J., Hirashima, M., Munn, D. H., Murphy, W. J., Azuma, M., Anderson, A. C., Kuchroo, V. K., & Blazar, B. R. (2011). Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood, 117(17), 4501-4510. https://doi.org/10.1182/blood-2010-10-310425