Differential effects of denileukin diftitox IL-2 immunotoxin on NK and regulatory T cells in nonhuman primates

Yohei Yamada, Akihiro Aoyama, Georges Tocco, Svjetlan Boskovic, Ognjenka Nadazdin, Alessandro Alessandrini, Joren C. Madsen, A. Benedict Cosimi, Gilles Benichou, Tatsuo Kawai

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20 Citations (Scopus)

Abstract

Denileukin diftitox (DD), a fusion protein comprising IL-2 and diphtheria toxin, was initially expected to enhance antitumor immunity by selectively eliminating regulatory T cells (Tregs) displaying the high-affinity IL-2R (α-β-γ trimers). Although DD was shown to deplete some Tregs in primates, its effects on NK cells (CD16 +CD8 +NKG2A +CD3 -), which constitutively express the intermediate-affinity IL-2R (β-γ dimers) and play a critical role in antitumor immunity, are still unknown. To address this question, cynomolgus monkeys were injected i.v. with two doses of DD (8 or 18 μg/kg). This treatment resulted in a rapid, but short-term, reduction in detectable peripheral blood resting Tregs (CD4 +CD45RA +Foxp3 +) and a transient increase in the number of activated Tregs (CD4 +CD45RA -Foxp3 high), followed by their partial depletion (50-60%). In contrast, all NK cells were deleted immediately and durably after DD administration. This difference was not due to a higher binding or internalization of DD by NK cells compared with Tregs. Coadministration of DD with IL-15, which binds to IL-2Rβ-γ, abrogated DD-induced NK cell deletion in vitro and in vivo, whereas it did not affect Treg elimination. Taken together, these results show that DD exerts a potent cytotoxic effect on NK cells, a phenomenon that might impair its antitumoral properties. However, coadministration of IL-15 with DD could alleviate this problem by selectively protecting potentially oncolytic NK cells, while allowing the depletion of immunosuppressive Tregs in cancer patients.

Original languageEnglish
Pages (from-to)6063-6070
Number of pages8
JournalJournal of Immunology
Volume188
Issue number12
DOIs
Publication statusPublished - 2012 Jun 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Yamada, Y., Aoyama, A., Tocco, G., Boskovic, S., Nadazdin, O., Alessandrini, A., Madsen, J. C., Cosimi, A. B., Benichou, G., & Kawai, T. (2012). Differential effects of denileukin diftitox IL-2 immunotoxin on NK and regulatory T cells in nonhuman primates. Journal of Immunology, 188(12), 6063-6070. https://doi.org/10.4049/jimmunol.1200656