IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice

Keith L Knutson, Yushe Dang, Hailing Lu, Jason Lukas, Bond Almand, Ekram Gad, Ehizoje Azeke, Mary L. Disis

Research output: Contribution to journalArticle

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Abstract

Studies in cancer patients have suggested that breast tumors recruit regulatory T cells (Tregs) into the tumor microenvironment. The extent to which local Tregs suppress antitumor immunity in breast cancer is unknown. We questioned whether inhibiting systemic Tregs with an IL-2 immunotoxin in a model of neu-mediated breast cancer, the neu-transgenic mouse, could impact disease progression and survival. As in human breast cancer, cancers that develop in these mice attract Tregs into the tumor microenvironment to levels of ∼10-25% of the total CD4+ T cells. To examine the role of Tregs in blocking immune-mediated rejection of tumor, we depleted CD4 +CD25+ T cells with an IL-2 immunotoxin. The treatment depleted Tregs without concomitant lymphopenia and markedly inhibited tumor growth. Depletion of Tregs resulted in a persistent antitumor response that was maintained over a month after the last treatment. The clinical response was immune-mediated because adoptive transfer of Tregs led to a complete abrogation of the therapeutic effects of immunotoxin treatment. Further, Treg down-modulation was accompanied by increased Ag-specific immunity against the neu protein, a self Ag. These results suggest that Tregs play a major role in preventing an effective endogenous immune response against breast cancer and that depletion of Tregs, without any additional immunotherapy, may mediate a significant antitumor response.

Original languageEnglish (US)
Pages (from-to)84-91
Number of pages8
JournalJournal of Immunology
Volume177
Issue number1
StatePublished - Jul 1 2006

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Immunotoxins
Regulatory T-Lymphocytes
Transgenic Mice
Interleukin-2
Breast Neoplasms
Tumor Microenvironment
Neoplasms
Immunity
T-Lymphocytes
Therapeutics
Lymphopenia
Adoptive Transfer
Therapeutic Uses
Immunotherapy
Disease Progression
Survival
Growth
Proteins

ASJC Scopus subject areas

  • Immunology

Cite this

IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice. / Knutson, Keith L; Dang, Yushe; Lu, Hailing; Lukas, Jason; Almand, Bond; Gad, Ekram; Azeke, Ehizoje; Disis, Mary L.

In: Journal of Immunology, Vol. 177, No. 1, 01.07.2006, p. 84-91.

Research output: Contribution to journalArticle

Knutson, Keith L ; Dang, Yushe ; Lu, Hailing ; Lukas, Jason ; Almand, Bond ; Gad, Ekram ; Azeke, Ehizoje ; Disis, Mary L. / IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice. In: Journal of Immunology. 2006 ; Vol. 177, No. 1. pp. 84-91.
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