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

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. Overall design: ATAC-seq of WT and Zbtb32-/- OT-I cells from B16-OVA tumors at day 30 post inoculation