Targeting EZH2 Selectively Alters Intratumoral Regulatory T Cells to Enhance Cancer Immunity
2018; American Association of Immunologists; Volume: 200; Issue: 1_Supplement Linguagem: Inglês
10.4049/jimmunol.200.supp.57.39
ISSN1550-6606
AutoresMichel DuPage, David Wang, Jason Quiros, Kelly Mahuron, Chien-Chun Steven Pai, Valeria Ranzani, Arabella Young, Stephanie Silveria, Tory Harwin, Arbi Abnousian, Massimiliano Pagani, Michael Rosenblum, Frédéric Van Gool, Lawrence Fong, Jeffrey A. Bluestone,
Tópico(s)T-cell and B-cell Immunology
ResumoAbstract Immunosuppressive regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Targeting Tregs may be a powerful means to unleash more potent immune responses against cancer, but targeting these cells is challenging because their generalized inactivation may incite severe autoimmune toxicities. To selectively target Tregs in tumors, we investigated the role of the H3K27 methyltransferase EZH2 in Tregs and determined that its enhanced activity at tumor sites in mice and humans leads to more robust and stable Tregs. We demonstrate that blocking EZH2 activity, both pharmacologically and genetically, selectively reprograms the function of tumor-infiltrating Tregs without systemically altering Treg function. Genetic disruption of EZH2 in tumor-resident Tregs led to their acquisition of pro-inflammatory functions that remodeled the tumor microenvironment and enhanced the recruitment and function of effector T cells, leading to the complete elimination of tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a novel strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity.
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