Integrated multiomics profiling identifies the differentiation program of regulatory T cells in human tumors [bulk ATAC-seq]

Regulatory T (Treg) cells suppress effective antitumor immunity in tumor-bearing hosts, thereby becoming promising targets in cancer immunotherapy. Here, we show that Treg cells in the tumor microenvironment (TME) of human lung cancers harbor a completely different open chromatin profile compared to effector T cells and peripheral Treg cells. The integrative sequencing analyses revealed that BATF, IRF4, NF-κb, and NR4A were important transcription factors for Treg cell differentiation in the TME. Particularly, 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. 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. Our results propose the specific chromatin remodeling and differentiation program of Treg cells in the TME, which can be applied in the development of Treg cell-targeted therapies. bulk ATAC-seq about T cell subsets (Treg cells, Tconv cells and CD8+ T cells) and T-cell leukemia/lymphoma (ATLL) cell lines.