SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ.

Abstract

Tumors convert conventional CD4(+) T cells into induced CD4(+)CD25(+)FoxP3(+) T regulatory (iTreg) cells that serve as an effective means of immune evasion. Therefore, the blockade of conventional CD4(+) T cell conversion into iTreg cells represents an attractive target for improving the efficacy of various immunotherapeutic approaches. Using a novel form of 4-1BBL molecule, SA-4-1BBL, we previously demonstrated that costimulation via 4-1BB receptor renders both CD4(+)and CD8(+) T effector (Teff) cells refractory to inhibition by Treg cells and increased intratumoral Teff/Treg cell ratio that correlated with therapeutic efficacy in various preclinical tumor models. Building on these studies, we herein show for the first time, to our knowledge, that signaling through 4-1BB inhibits antigen- and TGF-β-driven conversion of naïve CD4(+)FoxP3(-) T cells into iTreg cells via stimulation of IFN-γ production by CD4(+)FoxP3(-) T cells. Importantly, treatment with SA-4-1BBL blocked the conversion of CD4(+)FoxP3(-) T cells into Treg cells by EG.7 tumors. Taken together with our previous studies, these results show that 4-1BB signaling negatively modulate Treg cells by two distinct mechanisms: i) inhibiting the conversion of CD4(+)FoxP3(-) T cells into iTreg cells and ii) endowing Teff cells refractory to inhibition by Treg cells. Given the dominant role of Treg cells in tumor immune evasion mechanisms, 4-1BB signaling represents an attractive target for favorably tipping the Teff:Treg balance toward Teff cells with important implications for cancer immunotherapy.

• Authors: Shravan Madireddi, Rich-Henry Schabowsky, Abhishek K Srivastava, Rajesh K Sharma, Esma S Yolcu, Haval Shirwan
• Journal: PloS one (PLoS One) Vol. 7 Issue 8 Pg. e42459 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22870329 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 4-1BB Ligand
• Tumor Necrosis Factor Receptor Superfamily, Member 9
• Interferon-gamma

Topics

• 4-1BB Ligand (genetics, immunology)
• Animals
• CD8-Positive T-Lymphocytes (immunology)
• Immunotherapy
• Interferon-gamma (genetics, immunology)
• Mice
• Mice, Knockout
• Neoplasms, Experimental (genetics, immunology, therapy)
• Signal Transduction (immunology)
• T-Lymphocytes, Regulatory (immunology)
• Tumor Necrosis Factor Receptor Superfamily, Member 9 (genetics, immunology)