Poster abstracts
Poster number 25 submitted by Tong Xiao
Determine the role of ZFP148 in regulating CD8+ T cell effector differentiation and exhaustion
Tong Xiao (MCDB program), Johanna Schafer (Pelotonia Institute for Immuno-Oncology, OSUCCC James), Anjun Ma (Department of Biomedical Informatics, OSU), No-Joon Song (Pelotonia Institute for Immuno-Oncology, OSUCCC James), Qin Ma (Department of Biomedical Informatics, OSU), Zihai Li (Pelotonia Institute for Immuno-Oncology, OSUCCC James)
Abstract:
CD8+ T cell effector differentiation and exhaustion in the tumor microenvironment is transcriptionally and epigenetically controlled by a number of transcription factors (TFs) such as T cell factor 1 (TCF1) and TOX. Dissecting how these intracellular factors program the above process is critical for the reinvigoration of exhausted cells. Through bioinformatic inference on a single-cell RNA-sequencing dataset acquired on CD8+ tumor-infiltrating lymphocytes (TILs), we identified several TFs to be active in a TCF1+ progenitor exhausted CD8+ T cell population, which potentially give rise to more exhausted progenies. Among these TFs, Zinc-Finger Protein 148 (ZFP148) showed one of the strongest positive correlations with Tcf7 (codes for TCF1). ZFP148 is a TF reported to regulate cell proliferation and survival in embryonic fibroblasts and other cell types but has not been studied in T cell biology. During preliminary investigations, I have found that ZFP148 expression could be induced by T cell receptor (TCR) engagement in mouse primary CD8+ T cells cultured in vitro and is positively associated with the activation status and effector function of the cells. Genetic deletion of ZFP148 lead to a more activated cell state and greater effector cytokine production. After evaluating its expression in CD8+ TILs, ZFP148 was found to be expressed at the highest level in terminal exhausted cell population, suggesting a role for ZFP148 in the development of CD8+ T cell exhaustion. Further, by combining CRISPR KO ZBP148 in CD8+ T cells and adoptively transferring into tumor-bearing mice, I observed that ZFP148-deleted CD8+ T cells were not able to control tumor growth as efficiently as control CD8+ T cells. To further dissect the precise mechanism by which ZFP148 regulates CD8+ T cell effector differentiation and exhaustion, I will (1) untangle the downstream molecular targets of ZFP148 in CD8+ T cells, (2) determine the role of ZFP148 in regulating the anti-tumor function of CD8+ T cell.
References:
1. Chen, Z., et al., TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision. Immunity, 2019. 51(5): p. 840-855 e5.
2. Khan, O., et al., TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature, 2019. 571(7764): p. 211-218.
3. Im, S.J., et al., Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature, 2016. 537(7620): p. 417-421.
4. Merchant, J.L., et al., ZBP-89, a Kruppel-like zinc finger protein, inhibits epidermal growth factor induction of the gastrin promoter. Mol Cell Biol, 1996. 16(12): p. 6644-53.
5. Zou, Z.V., et al., Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway. Sci Rep, 2020. 10(1): p. 14156.
Keywords: Immuno-oncology, T cell exhaustion, Transcriptional regulation