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Zinc Finger and BTB Domain Containing 32 (Zbtb32) transcription factor promotes CD8+ T cell differentiation and function in cancer [RNA-Seq]

ABSTRACT: In the tumor microenvironment (TME), “exhausted” CD8+ T cells are classified into progenitor (Tpex) and terminally exhausted (Ttex) populations. Tpex cells could be reinvigorated during immune checkpoint blockade (ICB) therapy. However, the mechanisms governing the differentiation of Tpex to Ttex remain not well understood. In this study, we identified that Zinc Finger and BTB Domain Containing 32 (Zbtb32) transcription factor, highly expressed in CD8+ Ttex subset, plays a critical role in regulating CD8+ T cells within tumors. Zbtb32, regulated by CD28 signaling, promotes the differentiation of CD8+ T cells into Ttex subset, enhancing their cytotoxicity, proliferation and anti-tumor capability. Importantly, we found a competitive DNA binding between Zbtb32 and Bcl6, another Zbtb family member promoting the Tpex program, especially in regulation of Id2 expression. Thus, our findings underscore the pivotal role of Zbtb32 in CD8+ T cell anti-tumor function, with implications in cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE284604 | GEO | 2025/12/20

REPOSITORIES: GEO

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Project description:In chronic infections and cancer, exhausted CD8 T cells exhibit heterogeneous subpopulations. TCF1+PD-1+ progenitor exhausted CD8 T cells (Tpex) can self-renew and give rise to Tim-3+PD-1+ terminally differentiated CD8 T cells that retain their effector functions. Tpex cells are thus essential to maintaining a pool of antigen-specific CD8 T cells during persistent antigenic stimulation, and only they respond to PD-1-targeted therapy. Despite their potential as a crucial therapeutic target for immune interventions, the mechanisms controlling the maintenance of virus-specific Tpex cells remain to be determined. We observed approximately 10-fold fewer Tpex cells in the spleens of mice chronically infected with lymphocytic choriomeningitis virus (LCMV) one-year post-infection (p.i.) than at three months p.i. Similar to memory CD8 T cells, Tpex cells have been found to undergo self-renewal in the lymphoid organs, prominently the bone marrow, during chronic LCMV infection. Furthermore, ex vivo treatment with IL-15 preferentially induced the proliferation of Tpex cells rather than the terminally differentiated subsets. Interestingly, single-cell RNA sequencing analysis of LCMV-specific exhausted CD8 T cells after ex vivo IL-15 treatment compared with those before treatment revealed upregulation of ribosome-related genes and downregulation of genes associated with the TCR signaling pathway and apoptosis in both Tpex and Ttex subsets. The exogenous administration of IL-15 to chronically LCMV-infected mice also significantly increased self-renewal of Tpex cells in the spleen and bone marrow. In addition, we assessed the responsiveness of CD8 tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma patients to IL-15. Similar to the data we obtained from chronic viral infection in mice, the expansion of the Tpex subset of PD-1+ CD8 TILs upon ex vivo IL-15 treatment was significantly higher than that of the terminally differentiated subset. These results show that IL-15 could promote self-renewal of Tpex cells, which has important therapeutic implications.

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Zinc Finger and BTB Domain Containing 32 (Zbtb32) transcription factor promotes CD8+ T cell differentiation and function in cancer [RNA-Seq]

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