Overproduction of IFN gamma by Cbl-b-Deficient CD8(+) T Cells Provides Resistance against Regulatory T Cells and Induces Potent Antitumor Immunity

Regulatory T cells (Treg) are an integral component of the adaptive immune system that negatively affect antitumor immunity. Here, we investigated the role of the E3 ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) in establishing CD8(+) T-cell resistance to Treg-mediated suppression to enhance antitumor immunity. Transcriptomic analyses suggested that Cbl-b regulates pathways associated with cytokine signaling and cellular proliferation. We showed that the hypersecretion of IFN gamma by Cbl-b-deficient CD8(+) T cells selectively attenuated CD8(+) T-cell suppression by Tregs. Although IFN gamma production by Cbl-b-deficient T cells contributed to phenotypic alterations in Tregs, the cytokine did not attenuate the suppressive function of Tregs. Instead, IFN gamma had a profound effect on CD8(+) T cells by directly upregulating interferon-stimulated genes and modulating T-cell activation. In murine models of adoptive T-cell therapy, Cbl-b-deficient T cells elicited superior antitumor immune response. Furthermore, Cbl-b-deficient CD8(+) T cells were less susceptible to suppression by Tregs in the tumor through the effects of IFN gamma. Collectively, this study demonstrates that the hypersecretion of IFN gamma serves as a key mechanism by which Cbl-b-deficient CD8(+) T cells are rendered resistant to Tregs.