NR4A3 deficiency in CD8+ T cells improves adoptive T cell therapy of cancer

NR4A3 is a transcription factor that is rapidly induced in CD8+ T cells following antigenic recognition. We have previously shown that NR4A3 deficiency induces an early molecular program that promotes memory generation and enhances effector functions, which are two essential attributes for the success of adoptive cell therapy (ACT). Therefore, we tested the hypothesis that Nr4a3 -/- CD8+ T cells would have outstanding efficacy in ACT of cancer. Our results show that ACT of melanoma-bearing mice with Nr4a3 -/- effector CD8+ T cells provides a better tumor control than their wild-type counterpart. The therapeutic effect observed with Nr4a3 -/- effector CD8+ T cells is even better than the one observed with ACT of Nr4a3 +/+ effector CD8+ T cells in combination with anti-PD-L1 treatment. scRNA-seq analysis reveals a huge heterogeneity of tumor-infiltrating lymphocytes (TILs) states following ACT. The better tumor control observed with ACT of Nr4a3 -/- CD8+ effectors without anti-PD-L1 treatment correlates with an enrichment of TILs within the clusters that are associated with the anti-PD-L1 response of wild-type TILs. Moreover, the clusters that are enriched in Nr4a3 -/- TILs are the ones that are enriched for effector functions. Furthermore, Nr4a3 -/- and Nr4a3 +/+ effectors generate distinct progenitor populations. Pseudotime analysis suggests that these progenitors have different differentiation trajectories, which may explain why ACT with Nr4a3 -/- effectors is more efficient. Therefore, modulation of NR4A3 activity may represent a new strategy to generate long-lived and highly functional T cells for ACT. ### Competing Interest Statement The authors have declared no competing interest.