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

Q Zhou, ME Munger, RG Veenstra… - Blood, The Journal …, 2011 - ashpublications.org
Q Zhou, ME Munger, RG Veenstra, BJ Weigel, M Hirashima, DH Munn, WJ Murphy
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
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.
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