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

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.

• Authors: Aklile Berhanu, Jian Huang, Simon C Watkins, Hideho Okada, Walter J Storkus
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 178 Issue 6 Pg. 3400-8 (Mar 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17339434 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

• Animals
• Antigens, CD (immunology)
• Antigens, Differentiation, T-Lymphocyte (immunology)
• CD8-Positive T-Lymphocytes (immunology, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Cytokines (immunology, 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, pathology)
• Membrane Proteins (immunology, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Neoplasms, Experimental (immunology, pathology, therapy)
• Signal Transduction (immunology)
• T-Lymphocytes, Regulatory