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

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.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Andrea Pavesi

PROVIDER: PXD039542 | JPOST Repository | Thu Jan 19 00:00:00 GMT 2023

REPOSITORIES: jPOST

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

Lam Maxine S Y MSY Reales-Calderon Jose Antonio JA Ow Jin Rong JR Aw Joey J Y JJY Tan Damien D Vijayakumar Ragavi R Ceccarello Erica E Tabaglio Tommaso T Lim Yan Ting YT Chien Wang Loo WL Lai Fritz F Tanoto Anthony Tan AT Chen Qingfeng Q Sobota Radoslaw M RM Adriani Giulia G Bertoletti Antonio A Guccione Ernesto E Pavesi Andrea A

Nature communications 20230202 1

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 cytot ...[more]

PMID: 36732506

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