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Harnessing the IL-21-BATF Pathway in the CD8+ T Cell Anti-Tumor Response. Cancers (Basel) 2021 Mar 12;13(6)

Date

04/04/2021

Pubmed ID

33809259

Pubmed Central ID

PMC7998696

DOI

10.3390/cancers13061263

Scopus ID

2-s2.0-85102393382   1 Citation

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.

Author List

Topchyan P, Xin G, Chen Y, Zheng S, Burns R, Shen J, Kasmani MY, Kudek M, Yang N, Cui W

Authors

Weiguo Cui PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Matthew Kudek MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin