Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients.
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 IFNγ 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.
Department of Immunology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Chindu
C
Govindaraj
Mutsa
M
Madondo
Ying Ying
YY
Kong
Peter
P
Tan
Andrew
A
Wei
Magdalena
M
Plebanski
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D015870:Gene Expression; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D000077269:Lenalidomide; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D012008:Recurrence; D012074:Remission Induction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D007155:Immunologic Factors; D007376:Interleukin-2; D047889:Receptors, Tumor Necrosis Factor, Type II; D013792:Thalidomide; D007371:Interferon-gamma; D000077269:Lenalidomide; D001374:Azacitidine