Targeting Ezh2 selectively impairs intratumoral regulatory T cells to enhance cancer immunity
David Wang1,2, Jason Quiros2, Steven Pai4, Lawrence Fong3,4, Jeffrey A. Bluestone2,
The University of California San Francisco, Division of Pediatric Hematology/Oncology1, Diabetes Center2, Helen Diller Family Comprehensive Cancer Center3, Division of Hematology/Oncology4, Department of Microbiology and Immunology5
The epigenetic enzyme Ezh2 is critical for maintaining the stability and function of regulatory T cells (Tregs) upon activation. Here we show that this activity of Ezh2 can be exploited to specifically disrupt intratumoral Treg function without compromising systemic control of immune homeostasis. Mice with targeted deficiency of Ezh2 in all Tregs were resistant to the development of multiple cancers. Protection correlated with increased intratumoral infiltration of CD8+ T cells with enhanced function, as well as unstable Foxp3 expression and reduced frequencies of Tregs specifically in the tumor microenvironment. However, tumor immunity was not solely due to a loss of suppressive function by intratumoral Tregs. Instead, Ezh2 deficient Tregs acquired activities that promoted tumor clearance. First, acute disruption of Ezh2 in Tregs, using tamoxifen inducible alleles of Cre, increased the production of proinflammatory cytokines (IL-2 and IFN-g) from tumor infiltrating Tregs. Second, in a system where mice were co-populated with wild-type and Ezh2-deficient Tregs, the presence of Ezh2-deficient Tregs was sufficient to confer tumor control. Finally, mice with systemic depletion of Tregs, using a Foxp3-driven diphtheria toxin receptor model, did not reject tumors, but did exhibit severe, often lethal, autoimmune side effects, such toxicities were not observed with acute targeting of Ezh2 function in Tregs. Thus, disruption of Ezh2 in Tregs drives a unique phenotype among tumor infiltrating Tregs, reprogramming the tumor microenvironment and selectively augmenting the anti-tumor immune response. This work reveals the potential for pharmacologic inhibition of Ezh2 to create an unexpected synergy between targeting the oncogenic activities of Ezh2 in cancer cells and modulating immune cell function in the surrounding tumor microenvironment.