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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358 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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    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