Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients

Chindu Govindaraj, Mutsa Madondo, Ying Ying Kong, Peter Tan, Andrew Wei, Magdalena Plebanski

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A major limitation to improved outcomes in acute myelogenous leukemia (AML) is relapse resulting from leukemic cells that persist at clinical remission. Regulatory T cells (Tregs), which are increased in AML patients, can contribute to immune evasion by residual leukemic cells. Tumor necrosis factor (TNF), a pro-inflammatory cytokine present at high levels within patients, can induce TNF receptor-2 (TNFR2) expression on Tregs. We hypothesized that since TNFR2 is required for Treg stabilization and TNFR2+ Tregs are potent suppressors, targeting TNFR2+ Tregs may restore the effectiveness of immune-surveillance mechanisms. In this pilot study, we report AML patients in clinical remission have substantially increased levels of TNFR2+ T cells, including TNFR2+ Tregs and impaired effector CD4 T cell function with reduced IL-2 and IFN? production. The immunomodulatory drug, lenalidomide, and the demethylating agent, azacitidine have been moderately successful in treating AML patients, but their combined effects on TNFR2+ T cells, including Tregs are currently unknown. Our data indicates that although treatment with lenalidomide and azacitidine increased cytokine production by effector T cells in all patients, durable clinical remissions may be observed in patients with a concomitant reduction in TNFR2+ T cells and TNFR2+ Tregs. In vitro studies further demonstrated that lenalidomide can reduce TNFR2 expression and can augment effector cytokine production by T cells, which can be further enhanced by azacitidine. These results indicate that reduction of TNFR2+ T cells in AML postremission phase may result from combined azacitidine/lenalidomide therapy and may contribute to an improved clinical outcome
Original languageEnglish
Pages (from-to)795 - 802
Number of pages8
JournalAmerican Journal of Hematology
Volume89
Issue number8
DOIs
Publication statusPublished - 2014

Cite this

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title = "Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients",
abstract = "A major limitation to improved outcomes in acute myelogenous leukemia (AML) is relapse resulting from leukemic cells that persist at clinical remission. Regulatory T cells (Tregs), which are increased in AML patients, can contribute to immune evasion by residual leukemic cells. Tumor necrosis factor (TNF), a pro-inflammatory cytokine present at high levels within patients, can induce TNF receptor-2 (TNFR2) expression on Tregs. We hypothesized that since TNFR2 is required for Treg stabilization and TNFR2+ Tregs are potent suppressors, targeting TNFR2+ Tregs may restore the effectiveness of immune-surveillance mechanisms. In this pilot study, we report AML patients in clinical remission have substantially increased levels of TNFR2+ T cells, including TNFR2+ Tregs and impaired effector CD4 T cell function with reduced IL-2 and IFN? production. The immunomodulatory drug, lenalidomide, and the demethylating agent, azacitidine have been moderately successful in treating AML patients, but their combined effects on TNFR2+ T cells, including Tregs are currently unknown. Our data indicates that although treatment with lenalidomide and azacitidine increased cytokine production by effector T cells in all patients, durable clinical remissions may be observed in patients with a concomitant reduction in TNFR2+ T cells and TNFR2+ Tregs. In vitro studies further demonstrated that lenalidomide can reduce TNFR2 expression and can augment effector cytokine production by T cells, which can be further enhanced by azacitidine. These results indicate that reduction of TNFR2+ T cells in AML postremission phase may result from combined azacitidine/lenalidomide therapy and may contribute to an improved clinical outcome",
author = "Chindu Govindaraj and Mutsa Madondo and Kong, {Ying Ying} and Peter Tan and Andrew Wei and Magdalena Plebanski",
year = "2014",
doi = "10.1002/ajh.23746",
language = "English",
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pages = "795 -- 802",
journal = "American Journal of Hematology",
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Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients. / Govindaraj, Chindu; Madondo, Mutsa; Kong, Ying Ying; Tan, Peter; Wei, Andrew; Plebanski, Magdalena.

In: American Journal of Hematology, Vol. 89, No. 8, 2014, p. 795 - 802.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients

AU - Govindaraj, Chindu

AU - Madondo, Mutsa

AU - Kong, Ying Ying

AU - Tan, Peter

AU - Wei, Andrew

AU - Plebanski, Magdalena

PY - 2014

Y1 - 2014

N2 - A major limitation to improved outcomes in acute myelogenous leukemia (AML) is relapse resulting from leukemic cells that persist at clinical remission. Regulatory T cells (Tregs), which are increased in AML patients, can contribute to immune evasion by residual leukemic cells. Tumor necrosis factor (TNF), a pro-inflammatory cytokine present at high levels within patients, can induce TNF receptor-2 (TNFR2) expression on Tregs. We hypothesized that since TNFR2 is required for Treg stabilization and TNFR2+ Tregs are potent suppressors, targeting TNFR2+ Tregs may restore the effectiveness of immune-surveillance mechanisms. In this pilot study, we report AML patients in clinical remission have substantially increased levels of TNFR2+ T cells, including TNFR2+ Tregs and impaired effector CD4 T cell function with reduced IL-2 and IFN? production. The immunomodulatory drug, lenalidomide, and the demethylating agent, azacitidine have been moderately successful in treating AML patients, but their combined effects on TNFR2+ T cells, including Tregs are currently unknown. Our data indicates that although treatment with lenalidomide and azacitidine increased cytokine production by effector T cells in all patients, durable clinical remissions may be observed in patients with a concomitant reduction in TNFR2+ T cells and TNFR2+ Tregs. In vitro studies further demonstrated that lenalidomide can reduce TNFR2 expression and can augment effector cytokine production by T cells, which can be further enhanced by azacitidine. These results indicate that reduction of TNFR2+ T cells in AML postremission phase may result from combined azacitidine/lenalidomide therapy and may contribute to an improved clinical outcome

AB - A major limitation to improved outcomes in acute myelogenous leukemia (AML) is relapse resulting from leukemic cells that persist at clinical remission. Regulatory T cells (Tregs), which are increased in AML patients, can contribute to immune evasion by residual leukemic cells. Tumor necrosis factor (TNF), a pro-inflammatory cytokine present at high levels within patients, can induce TNF receptor-2 (TNFR2) expression on Tregs. We hypothesized that since TNFR2 is required for Treg stabilization and TNFR2+ Tregs are potent suppressors, targeting TNFR2+ Tregs may restore the effectiveness of immune-surveillance mechanisms. In this pilot study, we report AML patients in clinical remission have substantially increased levels of TNFR2+ T cells, including TNFR2+ Tregs and impaired effector CD4 T cell function with reduced IL-2 and IFN? production. The immunomodulatory drug, lenalidomide, and the demethylating agent, azacitidine have been moderately successful in treating AML patients, but their combined effects on TNFR2+ T cells, including Tregs are currently unknown. Our data indicates that although treatment with lenalidomide and azacitidine increased cytokine production by effector T cells in all patients, durable clinical remissions may be observed in patients with a concomitant reduction in TNFR2+ T cells and TNFR2+ Tregs. In vitro studies further demonstrated that lenalidomide can reduce TNFR2 expression and can augment effector cytokine production by T cells, which can be further enhanced by azacitidine. These results indicate that reduction of TNFR2+ T cells in AML postremission phase may result from combined azacitidine/lenalidomide therapy and may contribute to an improved clinical outcome

UR - http://onlinelibrary.wiley.com/doi/10.1002/ajh.23746/pdf

U2 - 10.1002/ajh.23746

DO - 10.1002/ajh.23746

M3 - Article

VL - 89

SP - 795

EP - 802

JO - American Journal of Hematology

JF - American Journal of Hematology

SN - 0361-8609

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ER -