Lam et al. demonstrated that transient treatment with the small molecule inhibitor (UNC0642) of the epigenetic regulator G9a/GLP during ex vivo expansion of T cells improved the cytotoxic capability of TCR-engineered T cells, CAR T cells, and NK cells. G9a/GLP inhibition increased granzyme expression without terminal T cell differentiation or exhaustion, and increased expression of genes and proteins involved in pro-inflammatory pathways, T cell activation, cytotoxicity, and mitochondrial respiration. In an orthotopic HCC mouse model, UNC0642 treatment improved antitumor activity of engineered TCR T cells.
Contributed by Shishir Pant
ABSTRACT: Engineered T cells transiently expressing tumor-targeting receptors are an attractive form of engineered T cell therapy as they carry no risk of insertional mutagenesis or long-term adverse side-effects. However, multiple rounds of treatment are often required, increasing patient discomfort and cost. To mitigate this, we sought to improve the antitumor activity of transient engineered T cells by screening a panel of small molecules targeting epigenetic regulators for their effect on T cell cytotoxicity. Using a model for engineered T cells targetting hepatocellular carcinoma, we find that short-term inhibition of G9a/GLP increases T cell antitumor activity in in vitro models and an orthotopic mouse model. G9a/GLP inhibition increases granzyme expression without terminal T cell differentiation or exhaustion and results in specific changes in expression of genes and proteins involved in pro-inflammatory pathways, T cell activation and cytotoxicity.
Author Info: (1) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. (2) Institute of Molecular and Cell Biology, Agency
Author Info: (1) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. (2) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. (3) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. (4) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. (5) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. (6) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. (7) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. (8) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. (9) Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A_STAR), 138673, Singapore, Singapore. (10) Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A_STAR), 138673, Singapore, Singapore. (11) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. (12) Duke-NUS Medical School, 169857, Singapore, Singapore. (13) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. (14) Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A_STAR), 138673, Singapore, Singapore. Bioinformatics Institute, Agency for Science, Technology and Research (A_STAR), 138671, Singapore, Singapore. (15) Singapore Immunology Network, Agency for Science and Technology (A*STAR), 138648, Singapore, Singapore. Department of Biomedical Engineering, National University of Singapore, 117583, Singapore, Singapore. (16) Duke-NUS Medical School, 169857, Singapore, Singapore. (17) Department of Oncological Sciences and Pharmacological Sciences, Center for Therapeutics Discovery, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 10029, New York, USA. (18) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. andreap@imcb.a-star.edu.sg. Mechanobiology Institute, National University of Singapore, 117411, Singapore, Singapore. andreap@imcb.a-star.edu.sg.
