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Yasuhiro Nagai, Mei Ji, Yan Xiao, Hongtao Zhang, Bin Li, Takuya Ohtani, Mark I Greene, PRMT5 is a novel cofactor of Foxp3 and can be a target for tumor immunotherapy, The Journal of Immunology, Volume 196, Issue 1_Supplement, May 2016, Page 211.7, https://doi.org/10.4049/jimmunol.196.Supp.211.7
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Abstract
Regulatory T cells (Tregs) are a subpopulation of T cells specialized for suppressing host immune systems, whose dysfunction can lead to severe autoimmunity and inflammatory disease in humans and animals. In a tumor bearing host, an enhanced activity of Tregs may limit host immunity against tumor antigens. Our laboratory has studied the Foxp3 transcriptional complex at the molecular and atomic levels. We identified a protein arginine methyl transferase 5 (PRMT5) as a binding partner of Foxp3. Mice whose expression of PRMT5 was deleted in Tregs developed severe autoimmunity, scurfy like phenotypes and died at ~3 weeks of age. A limited number of Tregs were found in the spleen, but there were normal numbers of Tregs in the peripheral lymph nodes. Tregs that lacked PRMT5 displayed limited suppressive function when compared to wild type cells. Two types of PRMT5 inhibitors, EPZ004777 and EPZ015666, were studied to determine if inhibition of PRMT5 reduces human Treg functions. While EPZ004777 could inhibit human Treg functions in vitro, EPZ015666 had limited ability to limit these Treg activities. EPZ004777 could also inhibit the methylation of Foxp3. Injection of EPZ004777 to p185/erbB2/neu tumor bearing mice enhanced the effect of anti-erbB2/neu monoclonal antibody therapy. Furthermore, treatment with EPZ004777 reduced the numbers of tumor infiltrating Tregs, indicating that EPZ004777 functions by inhibiting Treg functions and/or migration of Tregs into p185 expressing tumors. These studies support the concept that controlling PRMT5 activity is a promising strategy in a p185 targeted monoclonal antibody therapy in which host immunity against tumors is augmented in a Foxp3 dependent manner.
