IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice.
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 approximately 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.
Knutson
Keith L
KL
Department of Immunology, Mayo Clinic College of Medicine, 342C Guggenheim, 200 First Street SW, Rochester, MN 55905, USA. knutson.keith@mayo.edu
Dang
Yushe
Y
Lu
Hailing
H
Lukas
Jason
J
Almand
Bond
B
Gad
Ekram
E
Azeke
Ehizoje
E
Disis
Mary L
ML
D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D018734:Genes, erbB-2; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D000922:Immunotoxins / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use*; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D012259:Ribonuclease, Pancreatic / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
D014408:Biomarkers, Tumor; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000922:Immunotoxins; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; C412343:recombinant fusion protein RNase1-IL-2; D012259:Ribonuclease, Pancreatic