title: 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.affiliation: Institute for Cellular Therapeutics, Department of Microbiology and Immunology, and James Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Shravan
authors.initials: S
authors.lastname: Madireddi
authors.forename: Rich-Henry
authors.initials: RH
authors.lastname: Schabowsky
authors.forename: Abhishek K
authors.initials: AK
authors.lastname: Srivastava
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Sharma
authors.forename: Esma S
authors.initials: ES
authors.lastname: Yolcu
authors.forename: Haval
authors.initials: H
authors.lastname: Shirwan
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D007167:Immunotherapy; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma