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Recent successes in immune therapeutic strategies aimed to improve control over tumor growth have sparked hope that long-lived control of cancer through stimulation of the immune system can be possible. However, the underlying immunological mechanisms that are induced by immunotherapeutic strategies are not well understood. In this study, we used the highly immunogenic Friend virus-induced FBL-3 tumor as a model to study the mechanisms of immunological tumor control by CD4(+) T cells in the course of CD137 (4-1BB) agonist immunotherapy in the absence of a CD8 T cell response. We demonstrate that treatment with a CD137 agonist resulted in complete FBL-3 tumor regression in CD8(+) T cell-deficient mice. CD137 signaling enhanced the production of proinflammatory cytokines and cytotoxic molecules in tumor-specific CD4(+) T cells. Interestingly, a subset of CD4(+)Foxp3(+) regulatory T cells was reprogrammed to eliminate immunogenic virus-induced tumor cells in response to CD137 agonist treatment. These cells expressed markers characteristic for Th cells (CD154) and produced the cytokine TNF-α or the T-box transcriptional factor Eomesodermin and granzyme B without loss of Foxp3 expression. Foxp3 Eomes double-positive CD4(+) T cells were capable of eliminating immunogenic virus-induced tumor cells in vivo. Thus, our data show that tumor-induced Foxp3(+)CD4(+) T cells can be reprogrammed into cytotoxic effector cells upon therapeutic costimulatory signaling and restore antitumor immunity.

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity