G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered 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.
Related
- Uncovering the cytotoxicity and growth inhibition of 14 Microcystis extracts on freshwater fish cell lines
- Cooperative inhibition of mTORC1 disrupts iron–redox homeostasis and triggers ferritinophagy-dependent ferroptosis in hepatocellular carcinoma
- Selective granzyme B replenishment dominates the molecular switch for sustained cytotoxicity in effector CD8+ T lymphocytes
- Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense
- 263 Effects of resorcinyl isoprenyl benzene derivative IPI201 on natural killer cell cytotoxicity and tumor cell viability in human colorectal adenocarcinoma cells
BibTeX
@article{lam2026g9aglp,
title = {{G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma}},
author = {Maxine S. Y. Lam and Jose Antonio Reales-Calderon and Jin Rong Ow and Joey J. Y. Aw and Damien Tan and Ragavi Vijayakumar and Erica Ceccarello and Tommaso Tabaglio and Yan Ting Lim and Wang Loo Chien and Fritz Lai and Anthony Tan Tanoto and Qingfeng Chen and Radoslaw M. Sobota and Giulia Adriani and Antonio Bertoletti and Ernesto Guccione and Andrea Pavesi},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-023-36160-5},
url = {https://hal.science/hal-05776437v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma
AU - Maxine S. Y. Lam
AU - Jose Antonio Reales-Calderon
AU - Jin Rong Ow
AU - Joey J. Y. Aw
AU - Damien Tan
AU - Ragavi Vijayakumar
AU - Erica Ceccarello
AU - Tommaso Tabaglio
AU - Yan Ting Lim
AU - Wang Loo Chien
AU - Fritz Lai
AU - Anthony Tan Tanoto
AU - Qingfeng Chen
AU - Radoslaw M. Sobota
AU - Giulia Adriani
AU - Antonio Bertoletti
AU - Ernesto Guccione
AU - Andrea Pavesi
PY - 2026
DA - 2026/10/03
JO - Nature Communications
DO - 10.1038/s41467-023-36160-5
UR - https://hal.science/hal-05776437v1
AB - 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.
SN - 2041-1723
SN - 2041-1723
ER -