Conditional regulatory T-cell depletion releases adaptive immunity preventing carcinogenesis and suppressing established tumor growth

Cancer Res. 2010 Oct 15;70(20):7800-9. doi: 10.1158/0008-5472.CAN-10-1681. Epub 2010 Oct 5.

Abstract

Foxp3 is a central control element in the development and function of regulatory T cells (Treg), and mice expressing a diphtheria toxin (DT) receptor-enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus (DEREG mice) allow conditional and efficient depletion of Foxp3(+) Treg by DT injection. Herein, we use DEREG mice and a mouse model of carcinogenesis to show that conditional and effective Treg depletion can both protect mice from carcinogenesis by innate control, yet permanently eradicate a proportion of de novo-established tumors in mice in a largely CD8(+) T-cell- and IFN-γ-dependent manner. Tumors displayed a heterogeneous response to Treg depletion, and suppression of established tumors was accompanied by an increase in the tumor-infiltrating CD8(+) T-cell/B-cell ratio. Tumor rejection occurred in the absence of overt autoimmunity, suggesting that effective transient Treg depletion strategies may be therapeutic in at least a proportion of spontaneous tumors developing in the host.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Adenocarcinoma / prevention & control
  • Animals
  • B-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Division
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / prevention & control
  • Diphtheria Toxin
  • Forkhead Transcription Factors / genetics
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Lymphocyte Depletion*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / pathology
  • Ovalbumin / genetics
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Diphtheria Toxin
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Green Fluorescent Proteins
  • Ovalbumin