The Nuclear Receptor NR1B1/RARα Arrests the Differentiation of Anti‐Tumor Effector Cytotoxic T Cells

Abstract NR1B1/RARα expression is dynamically regulated in cytotoxic lymphocytes (CTLs) in tumors, but the importance of its expression in anti‐tumor CTLs remains unknown. RARα gene expression is upregulated in CTLs in tumor microenvironments (TME), but its protein expression is downregulated by retinoic acid. The role of RARα expression in regulating anti‐tumor effector CTL (Teff) differentiation is reported. Mice that over‐express RARα in T cells are defective in early Teff differentiation and fail to populate tumors. In contrast, RARα‐deficient CTLs are hyper‐active in making tumor‐populating Teff cells, suggesting that RARα represses Teff differentiation. Moreover, RARα negatively controls the trafficking receptor switch from the lymphoid to an effector type. Generation of chimeric antigen receptor (CAR) T cells with reduced RARα expression produces highly effective CAR T cells with enhanced anti‐tumor cytotoxicity. Mechanistically, upregulated RARα expression decreases the nuclear histone acetylase (HAT) activity, required for TCF1 to BATF transcription factor and trafficking switches during Teff differentiation. Additionally, RARα and BATF closely associate with each other on Teff‐associated genes on the chromatin for possible cross‐regulation. In sum, T cell‐expressed RARα is identified as a novel negative regulator and potential target of intervention in promoting anti‐cancer T cell immunity.