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

Abstract

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.

Stepwise acquisition of unique epigenetic signatures during differentiation of tissue Treg cells

“…This signature, combined with gene expression profiling and TCR fate mapping, allowed for the discovery of the human counterpart of murine tissue-repair Treg cells as a T follicular helper cell (T FH )-polarized CCR8 + BATF + subset of Treg cells, and also identified its circulating blood precursor cell in human blood ( 82 ). BATF has further been reported as an important transcription factor for Treg cell differentiation and activation not only in healthy tissue, but also in the tumor microenvironment ( 83 ). To which extend healthy tissue and tumor Treg cells share transcriptional and epigenetic programmes remains to be investigated in detail on a grand scale for different tissues and tumor entities.…”

Significance of regulatory T cells in cancer immunology and immunotherapy

“…42 In addition, it has been recently shown that Treg cells with highly activated and differentiated phenotypes are abundant in the TME. 43 While the activity of effector T cells is attenuated in the harsh TME, such as in hypoxic conditions, Treg cells vigorously suppress antitumor immune responses through a function of HIF-1α 44 (Figure 2). In terms of metabolism, antitumor immune cells, such as CD8 + T cells, mainly employ a glycolytic pathway for their activation and exhibit an impaired response in low-glucose conditions in the TME, which is developed through the glucose consumption by cancer cells (the Warburg effect).…”

“…Using a series of single-cell gene expression and epigenomic analyses, we demonstrated that the transcription factor BATF is essential for the activation/differentiation of Treg cells in the TME of patients with non-small cell lung cancer (NSCLC). 43 BATF may play a role as a super-enhancer 67 in the tumour-infiltrating eTreg cells by co-acting with various other transcription factors, such as NR4A1 and IRF4, which are important for the activation/differentiation of Treg cells.…”

“…Treg cells expand in the TME in an antigen‐specific manner and have a T cell receptor (TCR) repertoire different from conventional CD4 + T cells 42 . In addition, it has been recently shown that Treg cells with highly activated and differentiated phenotypes are abundant in the TME 43 . While the activity of effector T cells is attenuated in the harsh TME, such as in hypoxic conditions, Treg cells vigorously suppress antitumor immune responses through a function of HIF‐1α 44 (Figure 2).…”

“…While these reports revealed a clear association between Treg cells expressing certain molecules and immune suppression in the TME, the detailed mechanism(s) of Treg cell activation/differentiation in the TME remains unclear. Using a series of single‐cell gene expression and epigenomic analyses, we demonstrated that the transcription factor BATF is essential for the activation/differentiation of Treg cells in the TME of patients with non‐small cell lung cancer (NSCLC) 43 . BATF may play a role as a super‐enhancer 67 in the tumour‐infiltrating eTreg cells by co‐acting with various other transcription factors, such as NR4A1 and IRF4, which are important for the activation/differentiation of Treg cells.…”