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 population 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 regulate 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 unappreciated CD4⁺ T cell-derived IL-21-BATF axis that could provide therapeutic insights to enhance effector CD8⁺ T cell function to fight cancer.