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

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G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma
Title:
G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma
Journal Title:
Nature Communications
Publication Date:
02 February 2023
Citation:
Lam, M. S. Y., Reales-Calderon, J. A., Ow, J. R., Aw, J. J. Y., Tan, D., Vijayakumar, R., Ceccarello, E., Tabaglio, T., Lim, Y. T., Chien, W. L., Lai, F., Tanoto, A. T., Chen, Q., Sobota, R. M., Adriani, G., Bertoletti, A., Guccione, E., & Pavesi, A. (2023). G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-36160-5
Abstract:
AbstractEngineered 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.
License type:
Attribution 4.0 International (CC BY 4.0)
Funding Info:
This research / project is supported by the National Medical Research Council - Open Fund - Young Individual Research Grant
Grant Reference no. : OFYIRG18nov-0002

This research / project is supported by the National Research Foundation, Singapore - Competitive research programme
Grant Reference no. : NRF-CRP17-2017-06

This research / project is supported by the National Research Foundation, Singapore - NRF-SIS “SingMass”
Grant Reference no. : NA

This research is supported by core funding from: Institute of Molecular and Cell Biology
Grant Reference no. : SC15-R0039
Description:
ISSN:
2041-1723