Poster abstracts
Poster number 10 submitted by Tong Xiao
ZFP148 is a transcriptional repressor of cytolytic effector CD8+ T cell differentiation
Tong Xiao (Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center- James Cancer Center and Solove Research Institute, Columbus, OH 43210, USA), Xingyu Chen (Department of Urology, CedarsSinai Medical Center, Los Angeles, CA, USA), No-Joon Song (Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center- James Cancer Center and Solove Research Institute, Columbus, OH 43210, USA), Ryan J. Brown, Anjun Ma (Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer CenterJames Cancer Center and Solove Research Institute, Columbus, OH, USA), Jay K. Mandula (Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer CenterJames Cancer Center and Solove Research Institute, Columbus, OH, USA)
Abstract:
Progenitor CD8+ T cells differentiate into effector and exhausted progenies during chronic antigen stimulation; however, mechanisms that restrain exhaustion and sustain effector differentiation remain incompletely defined. Here we identified the transcription factor ZFP148 as a repressor of CD8+ T cell effector differentiation. ZFP148-deficient CD8+ T cells displayed increased frequency of cytolytic effector cells and reduced frequency of exhausted cells compared with Zfp148fl/fl controls during chronic viral infection. Mechanistically, ZFP148 limited the chromatin accessibility of effector-driving transcription factor motifs and directly repressed expression of the transcription factor KLF2. Furthermore, conditional ZFP148 ablation in CD8+ T cells synergized with programmed cell death-1 blockade to improve tumor control in syngeneic mouse models. Consistently, cancer patients with lower ZNF148 expression in tumor-infiltrating CD8+ T cells showed improved responsiveness to immunotherapies. Collectively, our study identifies ZFP148 as a transcriptional repressor of CD8+ T cell effector differentiation and highlights its therapeutic potential for enhancing antitumor immunity.
Keywords: CD8+ T cells, T cell exhaustion, Immuno-oncology