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

Research output: Contribution to journalArticle

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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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T-cells
Acute Myeloid Leukemia
T-Lymphocytes
Phenotype
Galectin 3
Galectins
Tumors
Ligands
Liver
Interleukin-2
Hematologic Neoplasms
Regulatory T-Lymphocytes
Tumor Burden
Knockout Mice
Cellular Immunity
Cytokines
Neoplasm Metastasis

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. / Zhou, Qing; Munger, Meghan E.; Veenstra, Rachelle G.; Weigel, Brenda J.; Hirashima, Mitsuomi; Munn, David H; Murphy, William J.; Azuma, Miyuki; Anderson, Ana C.; Kuchroo, Vijay K.; Blazar, Bruce R.

In: Blood, Vol. 117, No. 17, 28.04.2011, p. 4501-4510.

Research output: Contribution to journalArticle

Zhou, Q, Munger, ME, Veenstra, RG, Weigel, BJ, Hirashima, M, Munn, DH, Murphy, WJ, Azuma, M, Anderson, AC, Kuchroo, VK & Blazar, BR 2011, 'Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia', Blood, vol. 117, no. 17, pp. 4501-4510. https://doi.org/10.1182/blood-2010-10-310425
Zhou, Qing ; Munger, Meghan E. ; Veenstra, Rachelle G. ; Weigel, Brenda J. ; Hirashima, Mitsuomi ; Munn, David H ; Murphy, William J. ; Azuma, Miyuki ; Anderson, Ana C. ; Kuchroo, Vijay K. ; Blazar, Bruce R. / Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. In: Blood. 2011 ; Vol. 117, No. 17. pp. 4501-4510.
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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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AU - Weigel, Brenda J.

AU - Hirashima, Mitsuomi

AU - Munn, David H

AU - Murphy, William J.

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AU - Anderson, Ana C.

AU - Kuchroo, Vijay K.

AU - Blazar, Bruce R.

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AB - 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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