Treatment-enhanced CD4+Foxp3+ glucocorticoid-induced TNF receptor family related high regulatory tumor-infiltrating T cells limit the effectiveness of cytokine-based immunotherapy

J Immunol. 2007 Mar 15;178(6):3400-8. doi: 10.4049/jimmunol.178.6.3400.

Abstract

Regulatory T cells can suppress activated CD4+ and CD8+ T effector cells and may serve as an impediment to spontaneous or therapeutic type 1 antitumor immunity. In a previous study, we observed minimal therapeutic impact, but significantly enhanced T cell cross-priming and lesional infiltration of tumor-reactive CD8+ T cells into established CMS4 sarcomas after combined treatment of BALB/c mice with rFLt3 ligand (rFL) and recombinant GM-CSF (rGM-CSF). In this study, we show that this cytokine regimen also results in the profound enhancement of CD4+ tumor-infiltrating lymphocytes (TIL) expressing FoxP3, IL-10, and TGF-beta mRNA, with 50 or 90% of CD4+ TIL coexpressing the CD25 and glucocorticoid-induced TNFR family related molecules, respectively. Intracellular staining for Foxp3 protein revealed that combined treatment with rFL plus rGM-CSF results in a significant increase in CD4+Foxp3+ T cells in the spleen of both control and tumor-bearing mice, and that nearly half of CD4+ TIL expressed this marker. In addition, CD4+ TIL cells were of an activated/memory (ICOS(high)CD62L(low)CD45RB(low)) phenotype and were capable of suppressing allospecific T cell proliferation and IFN-gamma production from (in vivo cross-primed) anti-CMS4 CD8+ T cells in vitro, via a mechanism at least partially dependent on IL-10 and TGF-beta. Importantly, in vivo depletion of CD4+ T cells resulted in the ability of previously ineffective, rFL plus rGM-CSF therapy-induced CD8+ T cells to now mediate tumor regression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytokines / immunology
  • Cytokines / therapeutic use
  • Forkhead Transcription Factors / immunology*
  • Glucocorticoid-Induced TNFR-Related Protein / immunology*
  • Immunologic Memory* / drug effects
  • Immunotherapy
  • Inducible T-Cell Co-Stimulator Protein
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Membrane Proteins / immunology
  • Membrane Proteins / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / therapy
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Glucocorticoid-Induced TNFR-Related Protein
  • Icos protein, mouse
  • Inducible T-Cell Co-Stimulator Protein
  • Membrane Proteins
  • flt3 ligand protein