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

Abstract

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.

Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?

“…In the same murine model, CD137 signaling improved expression of pro-inflammatory cytokines and cytotoxic effector molecules in tumor-specific CD4 T cells, coincident with upregulation of Eomes and Tbox (151); these cells were able to kill virus-induced tumor cells in vivo . Moving in the preclinical direction of immunotherapy, EBNA1-specific CD4 T cells expressing effector cytokines and GzmB were induced following therapeutic EBV vaccination against rhEBNA1 fused to the herpes simplex virus glycoprotein D, in rhesus macaques infected with lymphocryptovirus (152).…”

Functional effects of chimeric antigen receptor co-receptor signaling domains in human Tregs

“…showing promotion of Treg proliferation and suppression (Lee et al, 2005;Sun et al, 2002;Zhang et al, 2007), and others showing that 4-1BB signaling inhibits Treg suppression (Akhmetzyanova et al, 2016;Buchan et al, 2018;Smith et al, 2011).…”

Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

“…More recent evidence suggests that costimulation with CD134 plus CD137 agonists can induce Tregs to adopt a cytotoxic CD4 + effector phenotype, expressing Eomes, Granzyme B (GzmB), and IFN-γ, while retaining Foxp3 expression 201 . Additionally, CD137 costimulated Foxp3 + Tregs that express Eomes and GzmB can kill tumor target cells 202 . Thus it appears that immunomodulatory mAb therapy can exploit Treg plasticity to reverse tumor-mediated immunosuppression and add to the overall effector T cell response (Table 4).…”