Harnessing the IL-21-BATF Pathway in the CD8(+) T Cell Anti-Tumor Response

SIMPLE SUMMARY: In cancer, CD8(+) T cells enter a state of dysfunction within the tumor that prevents them from targeting and killing tumor cells. Our study aims to uncover how CD8(+) T cells can be helped by CD4(+) T cells or modified in order to improve their effector function against cancer. Thus, allowing them to better fight and control tumors. Our work shows that the protein Basic Leucine Zipper ATF-Like Transcription Factor (BATF) may be a key regulator of CD8(+) T cells and their anti-tumor function. These findings can provide further insight for the development of novel therapeutic treatments for cancer patients. 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.