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

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

Automated summary

Research has shown that Treg cells in the TME undergo a distinct open chromatin profile, with key transcription factors including BATF, IRF4, NF-κB, and NR4A, among which BATF serves as a crucial regulator influencing the differentiation and activation of Treg cells in the TME through epigenetic control of activation-associated gene expression. BATF deficiency may inhibit tumor growth, and high levels of BATF expression are associated with poor prognosis.