2. Academic Validation
  3. LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade

LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade

  • Nat Commun. 2021 Nov 24;12(1):6831. doi: 10.1038/s41467-021-27179-7.
Yi Liu 1,  Brian Debo 1 2,  Mingfeng Li 3,  Zhennan Shi 1,  Wanqiang Sheng 4 5,  Yang Shi 6 7
Affiliations

Affiliations

  • 1 Division of Newborn Medicine and Epigenetics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
  • 2 Ludwig Institute for Cancer Research, University of Oxford, Oxford, OX3 7DQ, UK.
  • 3 Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, 06510, USA.
  • 4 Division of Newborn Medicine and Epigenetics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. wanqiang_sheng@zju.edu.cn.
  • 5 Institute of Immunology, and Department of Respiratory Disease of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China. wanqiang_sheng@zju.edu.cn.
  • 6 Division of Newborn Medicine and Epigenetics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. yang.shi@ludwig.ox.ac.uk.
  • 7 Ludwig Institute for Cancer Research, University of Oxford, Oxford, OX3 7DQ, UK. yang.shi@ludwig.ox.ac.uk.
PMID: 34819502 DOI: 10.1038/s41467-021-27179-7
Abstract

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.

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