核受体 NR1B1/RARα 阻滞抗肿瘤效应细胞毒性 T 细胞的分化

NR1B1/RAR expression is dynamically regulated in cytotoxic lymphocytes (CTLs) in tumors, but the importance of its expression in anti-tumor CTLs remains unknown. RAR gene expression is upregulated in CTLs in tumor microenvironments (TME), but its protein expression is downregulated by retinoic acid.

The role of RAR expression in regulating anti-tumor effector CTL (Teff) differentiation is reported. Mice that over-express RAR in T cells are defective in early Teff differentiation and fail to populate tumors. In contrast, RAR -deficient CTLs are hyper-active in making tumor-populating Teff cells, suggesting that RAR represses Teff differentiation.

Moreover, RAR negatively controls the trafficking receptor switch from the lymphoid to an effector type. Generation of chimeric antigen receptor (CAR) T cells with reduced RAR expression produces highly effective CAR T cells with enhanced anti-tumor cytotoxicity.

Mechanistically, upregulated RAR expression decreases the nuclear histone acetylase (HAT) activity, required for TCF1 to BATF transcription factor and trafficking switches during Teff differentiation.

Additionally, RAR and BATF closely associate with each other on Teff-associated genes on the chromatin for possible cross-regulation. In sum, T cell-expressed RAR is identified as a novel negative regulator and potential target of intervention in promoting anti-cancer T cell immunity.