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
chromatin 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-κB, and NR4A were important
transcription factors for Treg cell differentiation in the TME. In particular, 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 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 Treg cells in the TME, which can be applied in the development of Treg cell-targeted
therapies.