Harnessing the il‐21‐batf pathway in the cd8+ t cell anti‐tumor response

Abstract

In cancer, CD8+ T cells enter a dysfunctional state which prevents them from effectively targeting and killing tumor cells. Tumor‐infiltrating CD8+ T cells consist of a heterogeneous popu-lation of memory‐like progenitor, effector, and terminally exhausted cells that exhibit differing functional and self‐renewal capacities. Our recently published work has shown that interleukin (IL)‐ 21‐producing CD4+ T cells help to generate effector CD8+ T cells within the tumor, which results in enhanced tumor control. However, the molecular mechanisms by which CD4+ helper T cells regu-late the differentiation of effector CD8+ T cells are not well understood. In this study, we found that Basic Leucine Zipper ATF‐Like Transcription Factor (BATF), a transcription factor downstream of IL‐21 signaling, is critical to maintain CD8+ T cell effector function within the tumor. Using mixed bone marrow chimeras, we demonstrated that CD8+ T cell‐specific deletion of BATF resulted in impaired tumor control. In contrast, overexpressing BATF in CD8+ T cells enhanced effector function and resulted in improved tumor control, bypassing the need for CD4+ helper T cells. Transcriptomic analyses revealed that BATF‐overexpressing CD8+ T cells had increased expression of costimulatory receptors, effector molecules, and transcriptional regulators, which may contribute to their enhanced activation and effector function. Taken together, our study unravels a previously unappre-ciated CD4+ T cell‐derived IL‐21–BATF axis that could provide therapeutic insights to enhance ef-fector CD8+ T cell function to fight cancer.