Improved Effectiveness of Anti-CTLA-4 Therapy through Disruption of EZH2 Function in T Cells
Sangeeta Goswami1*, Irina Apostolou2, Jan Zhang1, Jill Skepner2, Swetha Anandhan1, Xuejun Zhang3, Patrick Trojer2, Ana Aparicio1, Sumit K Subudhi1, James P. Allison 3, 4, Hong Chen3, Hao Zhao3, Padmanee Sharma1, 3, 4, * 1Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 2Constellation Pharmaceuticals, 215 1st Street Suite 200, Cambridge, MA, 02142, USA;3Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 4Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Both immune cell and tumor cell intrinsic mechanisms contribute towards the effectiveness of immune checkpoint therapy. While tumor cell inherent pathways responsible for evading therapy mediated immune response have been explored at the genomic and epigenetic level, the immune cell inherent pathways are not completely understood. Here, we show that ipilimumab (anti-CTLA-4) therapy increases EZH2 expression in human T cells that inversely correlates with clinical outcome. Pharmacological inhibition of EZH2 show improved anti-tumor immunity with anti-CTLA-4 therapy. Detailed analyses of T cell subsets reveal that EZH2 inhibition led to improved cytotoxic activity of effector T cells and phenotypic and functional alterations of the regulatory T cells, with subsequent effector-like T cell profile. Collectively, our data suggest that targeting EZH2 improves T cell mediated anti-tumor immunity and increase effectiveness of anti-CTLA-4 therapy.
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