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Exhausted CD8+ T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients. Here, we demonstrate that histone demethylase LSD1 acts to enforce an epigenetic program in progenitor exhausted CD8+ T cells to antagonize the TCF1-mediated progenitor maintenance and to promote terminal differentiation. Consequently, genetic perturbation or small molecules targeting LSD1 increases the persistence of the progenitor exhausted CD8+ T cells, which provide a sustained source for the proliferative conversion to numerically larger terminally exhausted T cells with tumor-killing cytotoxicity, thereby leading to effective and durable responses to anti-PD1 therapy. Collectively, our findings provide important insights into epigenetic mechanisms that regulate T cell exhaustion and have important implications for durable immunotherapy.

Original publication




Journal article


Nature communications

Publication Date





Division of Newborn Medicine and Epigenetics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.


CD8-Positive T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Cell Line, Tumor, Animals, Mice, Transgenic, Humans, Mice, Neoplasms, Disease Models, Animal, Recombinant Proteins, Cell Proliferation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Female, Male, Hepatocyte Nuclear Factor 1-alpha, Histone Demethylases, HEK293 Cells, Programmed Cell Death 1 Receptor, Primary Cell Culture, DNA Demethylation, Immune Checkpoint Inhibitors