IL-2 Immunotoxin Therapy Modulates Tumor-Associated Regulatory T Cells and Leads to Lasting Immune-Mediated Rejection of Breast Cancers in neu-Transgenic Mice

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.

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

“…Whether CLL cells can actively induce T regs or whether disease progression in CLL is only a consequence of the given immunologic constitution of a patient cannot be answered by our study. With T regdepleting and T reg -increasing substances in hand, [28][29][30][31] we have the means to test this hypothesis in preclinical tumor models, such as the Tcl1-mouse model for CLL. 32,33 …”

Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target

“…A recent report supported this idea by demonstrating that denileukin diftitox-reduced T reg numbers, and overall suppression mediated by the CD4 þ CD25 þ cell population in a mouse model of breast cancer, with improved immunity and tumor regression. 38 The therapeutic effects of Ontak have also been investigated in a variety of neoplasms, including cutaneous T-cell leukemia/ lymphoma, 39 ovarian, breast, and pancreatic carcinomas. 40 Similarly, antibodies against T regs have been used in the management of malignant melanomas with promising results.…”

Resveratrol analogue HS-1793 induces the modulation of tumor-derived T cells

“…Indeed, our previous study demonstrated that Treg cell depletion, treated by a low dose of cyclophosphamide, potentiated the antitumor effect of immunization with an injection of immature dendritic cells into irradiated tumors (31). As well as in breast cancer, Treg cells were increased in the peripheral blood and greatly increased in the tumor microenvironment (32); the presence of Treg cells is likely to correlate with cancer progression (33), and specific depletion of Treg cells markedly inhibits tumor growth and maintains a strong and persistent antitumor immune response (34).…”