BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors

Regulatory T (T_reg) cells suppress effective antitumor immunity in tumor-bearing hosts, thereby becoming promising targets in cancer immunotherapy. Despite the importance of T_reg cells in tumor immunity, little is known about their differentiation process and epigenetic profiles in the tumor microenvironment (TME). Here, we showed that T_reg cells in the TME of human lung cancers harbored a completely different open chromatin profile compared with CD8⁺ T cells, conventional CD4⁺ T cells in the TME, and peripheral T_reg cells. The integrative sequencing analyses including ATAC, single-cell RNA, and single-cell ATAC sequencing revealed that BATF, IRF4, NF-κB, and NR4A were important transcription factors for T_reg cell differentiation in the TME. In particular, BATF was identified as a key regulator, which leveraged T_reg cell differentiation through epigenetically controlling activation-associated gene expression, resulting in the robustness of T_reg cells in the TME. The single-cell sequencing approaches also revealed that tissue-resident and tumor-infiltrating T_reg cells followed a common pathway for differentiation and activation in a BATF-dependent manner heading toward T_reg cells with the most differentiated and activated phenotypes in tissues and tumors. BATF deficiency in T_reg cells remarkably inhibited tumor growth, and high BATF expression was associated with poor prognosis in lung cancer, kidney cancer, and melanoma. These findings indicate one of the specific chromatin remodeling and differentiation programs of T_reg cells in the TME, which can be applied in the development of T_reg cell-targeted therapies.