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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.

SA-4-1BBL Costimulation Inhibits Conversion of Conventional CD4+ T Cells into CD4+FoxP3+ T Regulatory Cells by Production of IFN-γ