NR4A1 transcriptionally regulates the differentiation of stem-like CD8+ T cells in the tumor microenvironment (RNA-Seq)

CD8+ T cells are rendered exhausted in tumor and chronic infection. Among heterogeneous exhausted T cells, a subpopulation of progenitor-like (Tpex) cells have been found important for long-term tumor or pathogen control, and are also the main responders in immunotherapy. Using a new reporter mouse for the orphan nuclear receptor NR4A1, originally characterized critical in T cell dysfunction, we discover that the reporter is highly expressed in Tpex cells in tumor and chronic infection. Enforced expression of Nr4a1 promotes Tpex cell accumulation, whereas tumor control is improved after Nr4a1 deletion, associated with increased effector function but decreased long-term maintenance of CD8+ T cells. Integrating ChIP-seq and RNA-seq analysis, NR4A1 is found to bind and promote the expression of Tpex-related genes, and suppresses terminal differentiation-associated genes. This study therefore has identified a key role of NR4A1 in Tpex regulation and provides a promising target for immunotherapy.