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Sci Immnuo BATF activates tumor-infiltrating regulatory T cells

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Immunotherapy, especially immune checkpoint inhibitors, is a typical case of the immune system fighting tumors [1,2,3].

Although effector T cells containing CD8+ T cells can inhibit tumors in healthy people and delay tumor growth to a certain extent in tumor patients, tumor lesions also have a variety of immunosuppressive mechanisms to cope with the above effects
.
The anti-tumor immune response is antagonized by a variety of immunosuppressive cells and molecules, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages; Molecules include CTLA-4 (cytotoxic T lymphocyte–associated antigen 4), PD-1 (programmed cell death-1), and PD-L1 (PD ligand 1).
【4】
。
FoxP3+CD4+ regulatory T cells are a subset of CD4+ T cells with immunosuppressive effects, which play a crucial role in maintaining immune homeostasis [5].

In the tumor microenvironment, regulatory T cells differentiate into highly activated phenotypes and promote tumor growth by effectively attenuating the anti-tumor immune response [6,7].

In animal models, clearing regulatory T cells or weakening their immunosuppressive function can effectively suppress tumors [8,9].

Therefore, a variety of interventions targeting regulatory T cells have gradually entered the clinical trial stage, but none of them have been successful
.
The regulatory T cell phenotype is not stable, and there are transient induced or regulatory T cells that express FoxP3 but do not have immunosuppressive function in the tumor microenvironment, so it is necessary
to deeply and accurately explore the tumor invasion of regulatory T cells.

At present, epigenetic profiles and transcription profiles of tumor-infiltrating immune cells to obtain tumor-specific phenotypes have been studied in depth, especially in
CD8+ T cells.
It can effectively remove tumor cells, but in the immunosuppressed tumor microenvironment, its killing function will gradually decay, a process also known as T cell depletion
.
In contrast, the mechanism of differentiation and activation of regulatory T cells in the tumor microenvironment and the epigenetic profile are still poorly
understood.
One of the research constraints is the scarcity of regulatory T cells in human tumor samples and the inclusion of both inhibitory and non-inhibitory subtypes, so there is a lack of effective research methods
.

BATF (Basic leucine zipper ATF-like transcription factor) is an activator protein-1 A member of the family that plays a key role
in cell types such as B cells, CD8+ T cells, and TH17 cells.
BATF can also maintain the function of tissue-resident regulatory T cells, but the effect on the function of tumor invasion regulatory T cells is still unknown
.
Recently, Hiroyoshi Nishikawa's research group from the National Cancer Center in Japan published a report in Science Immunology titled BATF epigenetically and transcriptionally controls the activation program of regulatory T The article Cells in Human Tumors found that BATF can also regulate the function of
tumor invasion regulatory T cells.

First, the authors collected regulatory T cells in the tumor microenvironment of human lung cancer, constructed a chromatin accessibility map of tumor infiltrating regulatory T cells by ATAC-seq method, and found that these cells had a high immunosuppressive phenotype
。 The authors also identified several DNA regulatory elements by comparing ATAC-seq peaks and gene expression profiles, and identified possible transcription factors
involved in the differentiation of tumor-infiltrating regulatory T cells by methods such as Motif enrichment and footprint analysis.

Next, the authors analyzed these transcription factors in depth and found that BATF tended to bind to chromatin regions of tumor-infiltrating regulatory T cells and upregulated their accessibility
.
Subsequently, by methods such as single-cell sequencing, it was determined that in tumors, BATF plays a role
in the early stages of regulatory T cell differentiation.

Finally, the authors determined through animal models and other methods that the deletion of BATF in regulatory T cells can significantly inhibit tumor growth
.
BATF regulates the activation-associated molecules of tumor-infiltrating regulatory T cells and is involved in reconstructing epigenetic states
.

In summary, the authors determined through the ATAC-seq method that regulatory T cells in the tumor microenvironment of human lung cancer have a unique epigenetic profile, and found that transcription factors such as BATF have changed to a key role
in regulatory T cell differentiation.

Article source

https://doi.
org/10.
1126/sciimmunol.
abk0957

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