期刊
LEUKEMIA
卷 35, 期 1, 页码 156-168出版社
SPRINGERNATURE
DOI: 10.1038/s41375-020-0794-0
关键词
-
资金
- Leukemia & Lymphoma Society Translational Research Program Award [6542-18]
- Takeda Oncology
Novel targeted agents in lymphoid malignancies therapy have complex immune effects, particularly through modulation of NF-kappa B signaling and T-cell function by targeting NEDD8-activating enzyme. This approach may offer potential therapeutic benefits by altering the immune response and tumor microenvironment.
Novel targeted agents used in therapy of lymphoid malignancies, such as inhibitors of B-cell receptor-associated kinases, are recognized to have complex immune-mediated effects. NEDD8-activating enzyme (NAE) has been identified as a tractable target in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. We and others have shown that pevonedistat (TAK-924), a small-molecule inhibitor of NAE, abrogates NF-kappa B signaling in malignant B cells. However, NF-kappa B pathway activity is indispensable in immune response, and T-cell function is altered in patients with CLL. Using T cells derived from patients with CLL, we demonstrate that although targeting NAE results in markedly differential expression of NF-kappa B-regulated genes and downregulation of interleukin (IL)-2 signaling during T-cell activation, T cells evade apoptosis. Meanwhile, NAE inhibition favorably modulates polarization of T cells in vitro, with decreased T-reg differentiation and a shift toward T(H)1 phenotype, accompanied by increased interferon-gamma production. These findings were recapitulated in vivo in immunocompetent mouse models. T cells exposed to pevonedistat in washout experiments, informed by its human pharmacokinetic profile, recover NAE activity, and maintain their response to T-cell receptor stimulation and cytotoxic potential. Our data shed light on the potential immune implications of targeting neddylation in CLL and lymphoid malignancies.
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