Tcf7, also known as Transcription Factor 7, is a gene expressed in immune cells. It is involved in the Wnt/β -catenin signaling pathway, which plays a crucial role in multiple biological processes such as cell differentiation, development, and homeostasis. Tcf7 has been associated with the regulation of immune responses and is thought to be important in maintaining the stem-like properties of certain T-cell subsets [2,3].

In oral cancer, TCF1/TCF7+ T cells are associated with tertiary lymphoid structures/organs and a superior prognosis. These cells express high levels of TLS-related genes and low levels of immune checkpoint molecules, suggesting they could be a new therapeutic target and prognostic marker [1]. In CD8+ T cells, Tcf7hi effector cells, which express high amounts of Tcf7, can give rise to central memory CD8+ T cells in the absence of cytotoxic differentiation, with Tcf1 (encoded by Tcf7) counteracting the differentiation of these cells and sustaining stem-cell-like genes [2]. A microbial metabolite, indole-3-propionic acid (IPA), can modulate the stemness program of CD8+ T cells by increasing H3K27 acetylation at the super-enhancer region of Tcf7, enhancing the efficacy of αPD-1 immunotherapy in pan-cancer [3]. In melanoma, the presence of TCF7 within CD8+ T cells in fixed tumor samples predicted positive clinical outcome in checkpoint-treated patients [4]. In mice, Tcf7 expression is not essential for glucose homeostasis as inactivation of Tcf7 in hepatocytes or β-cells did not impair glucose-related metabolic functions [5]. In colorectal cancer, DHA inhibits cancer development through the GSK-3β/TCF7/MMP9 pathway [6]. In hypertrophy of ligamentum flavum, TCF7 promotes the hyper-proliferation and fibrosis phenotype by interacting with SNAI2, and this is regulated by a miR-4306 feedback loop [7]. In vitro, Tcf7 promoter DNA methylation contributes to TCF1 downregulation in exhausted CD8+ T cells [8].

In conclusion, Tcf7 plays diverse and significant roles in immune-related functions, especially in T-cell regulation, and has implications in various diseases such as cancer and potentially in the context of immunotherapy. Studies using mouse models, like those exploring Tcf7 inactivation in specific cell types, have been valuable in understanding its non-essential role in glucose homeostasis and its potential as a therapeutic target in different disease areas.

References:

1. Peng, Yu, Xiao, Liping, Rong, Haixu, Fan, Song, Li, Jinsong. 2021. Single-cell profiling of tumor-infiltrating TCF1/TCF7+ T cells reveals a T lymphocyte subset associated with tertiary lymphoid structures/organs and a superior prognosis in oral cancer. In Oral oncology, 119, 105348. doi:10.1016/j.oraloncology.2021.105348. https://pubmed.ncbi.nlm.nih.gov/34044317/

2. Pais Ferreira, Daniela, Silva, Joana Gomes, Wyss, Tania, Speiser, Daniel E, Held, Werner. 2020. Central memory CD8+ T cells derive from stem-like Tcf7hi effector cells in the absence of cytotoxic differentiation. In Immunity, 53, 985-1000.e11. doi:10.1016/j.immuni.2020.09.005. https://pubmed.ncbi.nlm.nih.gov/33128876/

3. Jia, Dingjiacheng, Wang, Qiwen, Qi, Yadong, Chen, Shujie, Wang, Liangjing. 2024. Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer. In Cell, 187, 1651-1665.e21. doi:10.1016/j.cell.2024.02.022. https://pubmed.ncbi.nlm.nih.gov/38490195/

4. Sade-Feldman, Moshe, Yizhak, Keren, Bjorgaard, Stacey L, Getz, Gad, Hacohen, Nir. . Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. In Cell, 175, 998-1013.e20. doi:10.1016/j.cell.2018.10.038. https://pubmed.ncbi.nlm.nih.gov/30388456/

5. Kaur, Kiran Deep, Wong, Chi Kin, Baggio, Laurie L, Cao, Xiemin, Drucker, Daniel J. 2021. TCF7 is not essential for glucose homeostasis in mice. In Molecular metabolism, 48, 101213. doi:10.1016/j.molmet.2021.101213. https://pubmed.ncbi.nlm.nih.gov/33741532/

6. Dai, Xiaoshuo, Chen, Wei, Qiao, Yan, Dong, Ziming, Lu, Jing. 2023. Dihydroartemisinin inhibits the development of colorectal cancer by GSK-3β/TCF7/MMP9 pathway and synergies with capecitabine. In Cancer letters, 582, 216596. doi:10.1016/j.canlet.2023.216596. https://pubmed.ncbi.nlm.nih.gov/38101610/

7. Duan, Yang, Li, Jianjun, Qiu, Sujun, Ni, Songjia, Cao, Yanlin. 2022. TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum. In Journal of translational medicine, 20, 468. doi:10.1186/s12967-022-03677-0. https://pubmed.ncbi.nlm.nih.gov/36224570/

8. Zhao, Manzhi, Kiernan, Caoimhe H, Stairiker, Christopher J, Mueller, Yvonne M, Katsikis, Peter D. 2020. Rapid in vitro generation of bona fide exhausted CD8+ T cells is accompanied by Tcf7 promotor methylation. In PLoS pathogens, 16, e1008555. doi:10.1371/journal.ppat.1008555. https://pubmed.ncbi.nlm.nih.gov/32579593/