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

Yi Liu, Brian Debo, Mingfeng Li, Zhennan Shi, Wanqiang Sheng () and Yang Shi ()
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Yi Liu: Harvard Medical School
Brian Debo: Harvard Medical School
Mingfeng Li: Yale School of Medicine
Zhennan Shi: Harvard Medical School
Wanqiang Sheng: Harvard Medical School
Yang Shi: Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27179-7

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