Targeting the c-Rel Subunit of NF-κB Inhibits Treg Function in Melanoma

Regulatory T cells (Treg) suppress antitumor immune responses, are highly enriched in patients with melanoma, and are associated with a poor prognosis. Understanding the regulation of Treg homeostasis may provide insight for the development of effective immunotherapy. The transcription factor NF-κB is essential for thymic Treg development. NF-κB functions as a heterodimer with canonical signaling through p50–p65 or p50–c-Rel heterodimers. Although p65 deletion is embryonically lethal, the c-Rel containing NF-κB complexes have a more specialized function in the immune response, prompting Grinberg-Bleyer and colleagues to hypothesize that specific targeting of c-Rel NF-κB complexes might suppress Treg activity in cancer without the toxicity of less-specific NF-κB inhibitors. c-Rel, but not p65, was essential for the maintenance of activated Tregs (aTreg) in mice, and NF-κB c-Rel regulated aTreg differentiation and gene expression. In multiple mouse models of melanoma, deletion of c-Rel suppressed melanoma growth by inhibiting Treg activity and promoting the antitumor immune response, whereas deletion of p65 had little effect. The FDA-approved drug pentoxifylline has been shown to inhibit c-Rel in T cells, and it specifically reduced c-Rel levels without affecting p65. Pentoxifylline treatment reduced expression of Treg markers including Foxp3 and Helios, which could be rescued by c-Rel overexpression. Further, pentoxifylline treatment or c-Rel depletion resulted in downregulation of Treg-associated genes, and enrichment of resting Treg (rTreg) genes over aTreg genes, indicating that c-Rel inhibition impairs Treg identity. Consistent with these findings, pentoxifylline reduced melanoma growth in vivo and was associated with increased T-cell infiltration and reduced Treg function. Another c-Rel inhibitor, IT-603, had similar effects. In addition, pentoxifylline treatment further suppressed melanoma growth in combination with anti–PD-1 therapy, suggesting the potential for combination therapy. These findings suggest that specific c-Rel inhibition may suppress Treg function in the tumor microenvironment to suppress melanoma growth and potentially enhance the efficacy of immune checkpoint blockade.

Grinberg-Bleyer Y, Oh H, Desrichard A, Bhatt DM, Caron R, Chan TA, et al. NF-κB c-Rel Is crucial for the regulatory T cell immune checkpoint in cancer. Cell 2017;170:1096–1108.e13.

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