G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma

Maxine S. Y. Lam, Jose Antonio Reales-Calderon, Jin Rong Ow, Joey J. Y. Aw, Damien Tan, Ragavi Vijayakumar, Erica Ceccarello, Tommaso Tabaglio, Yan Ting Lim, Wang Loo Chien, Fritz Lai, Anthony Tan Tanoto, Qingfeng Chen, Radoslaw M. Sobota, Giulia Adriani, Antonio Bertoletti, Ernesto Guccione and Andrea Pavesi ()
Additional contact information
Maxine S. Y. Lam: Agency for Science, Technology and Research (A*STAR)
Jose Antonio Reales-Calderon: Agency for Science, Technology and Research (A*STAR)
Jin Rong Ow: Agency for Science, Technology and Research (A*STAR)
Joey J. Y. Aw: Agency for Science, Technology and Research (A*STAR)
Damien Tan: Agency for Science, Technology and Research (A*STAR)
Ragavi Vijayakumar: Agency for Science, Technology and Research (A*STAR)
Erica Ceccarello: Agency for Science, Technology and Research (A*STAR)
Tommaso Tabaglio: Agency for Science, Technology and Research (A*STAR)
Yan Ting Lim: Technology and Research (A∗STAR)
Wang Loo Chien: Technology and Research (A∗STAR)
Fritz Lai: Agency for Science, Technology and Research (A*STAR)
Anthony Tan Tanoto: Duke-NUS Medical School
Qingfeng Chen: Agency for Science, Technology and Research (A*STAR)
Radoslaw M. Sobota: Technology and Research (A∗STAR)
Giulia Adriani: Agency for Science and Technology (A*STAR)
Antonio Bertoletti: Duke-NUS Medical School
Ernesto Guccione: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Andrea Pavesi: Agency for Science, Technology and Research (A*STAR)

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36160-5

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