The Potential of T Cell Factor 1 in Sustaining CD8(+) T Lymphocyte-Directed Anti-Tumor Immunity

SIMPLE SUMMARY: The transcription factor T cell factor 1 (TCF1), encoded by the TCF7 gene, is a key regulator of T-cell fate, which is known to promote T cell proliferation and establish T cell stemness. Importantly, increasing evidence has demonstrated that TCF1 is a critical determinant of the success of anti-tumor immunotherapy, implicating that TCF1 is a promising biomarker and therapeutic target in cancer. In recent years, new findings have emerged to provide a clearer view of TCF1 and its role in T cell biology. In this review, we aim to provide a comprehensive outline of the most recent literature on the role of TCF1 in T cell development and to discuss the potential of TCF1 in sustaining CD8(+) T lymphocyte-directed anti-tumor immunity. ABSTRACT: T cell factor 1 (TCF1) is a transcription factor that has been highlighted to play a critical role in the promotion of T cell proliferation and maintenance of cell stemness in the embryonic and CD8(+) T cell populations. The regulatory nature of TCF1 in CD8(+) T cells is of great significance, especially within the context of T cell exhaustion, which is linked to the tumor and viral escape in pathological contexts. Indeed, inhibitory signals, such as programmed cell death 1 (PD-1) and cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), expressed on exhausted T lymphocytes (T(EX)), have become major therapeutic targets in immune checkpoint blockade (ICB) therapy. The significance of TCF1 in the sustenance of CTL-mediated immunity against pathogens and tumors, as well as its recently observed necessity for an effective anti-tumor immune response in ICB therapy, presents TCF1 as a potentially significant biomarker and/or therapeutic target for overcoming CD8(+) T cell exhaustion and resistance to ICB therapy. In this review, we aim to outline the recent findings on the role of TCF1 in T cell development and discuss its implications in anti-tumor immunity.