Batf-mediated Epigenetic Control of Effector CD8+ T Cell Differentiation

Tsao, Hsiao-Wei; Kaminski, James J.; Kurachi, Makoto; Barnitz, R. Anthony; DiIorio, Michael; LaFleur, Martin W.; Ise, Wataru; Kurosaki, Tomohiko; Wherry, E. John; Haining, W. Nicholas; Yosef, Nir

doi:10.1101/2021.01.04.425241

Cited by 3 publications

(4 citation statements)

References 116 publications

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“…In addition, the well-known function of BATF in T H 17 and CD8 + T cells is the recruitment of IRF4 to the AP-1–IRF composite element sites. Our data confirmed that whereas BATF and IRF4 cooperate, the gene expression of BATF was broadly up-regulated in tumor-infiltrating T reg cells compared with that of IRF4, suggesting more comprehensive roles of BATF in T reg cells, as reported in effector CD8 + T cells ( 46 ).…”

Section: Discussionsupporting

confidence: 82%

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

Itahashi¹,

Irie²,

Yuda

et al. 2022

Sci. Immunol.

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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.

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Section: Discussionsupporting

confidence: 82%

“…Given that BATF and IRF4 work together ( 45 , 46 ), the relationship between BATF and IRF4 binding regions was examined. In cluster 5, almost all IRF4 peaks overlapped with the BATF ChIP-seq peaks, suggesting that BATF and IRF4 may work together in certain differentiations of tumor-infiltrating T reg cells.…”

Section: Resultsmentioning

confidence: 99%

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

Itahashi¹,

Irie²,

Yuda

et al. 2022

Sci. Immunol.

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“…Moreover, Tsao et al evaluated the transcriptome and epigenome of differentiating CD8 + T cells in mice, highlighting the central role of BATF. Through genome-scale profiling, they observed that BATF induces transcriptional changes in stimulated naïve cells and establishes the effector cell transcriptional and epigenetic program through the cooperation with a network of TFs (Irf4, RUNX3 and T-bet) [126]. The HMT SUV39h is responsible for H3K9me3, driving transcriptional silencing [127].…”

Section: Epigenetic Mechanisms Underlying Cd8 + T Cell Functionsmentioning

confidence: 99%

Epigenetics: An opportunity to shape innate and adaptive immune responses

et al. 2022

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Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post‐translational modifications and the regulation of chromatin accessibility by non‐coding RNAs, all of which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental‐driven nature, piloting myeloid and lymphoid cell fate decisions with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage‐specific transcription factors and maintenance of cell type‐specific epigenetic modifications, referred to as ‘epigenetic memory’, dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells. Moreover, metabolic and epigenetic reprogramming occurring during a primary innate immune response leads to enhanced responses to secondary challenges, a phenomenon known as ‘trained immunity’. Here, we discuss how stable and dynamic epigenetic states control immune cell identity and plasticity in physiological and pathological conditions. Dissecting the regulatory circuits of cell fate determination and maintenance is of paramount importance for understanding the delicate balance between immune cell activation and tolerance, in healthy conditions and in autoimmune diseases.

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“…VIPER successfully profiled delicate differences between subpopulations and between MPR and Non (Figures 3B-D). BATF2, upregulated in CD8.c05 cells in the MPR (Figure 3B), was shown to be essential for epigenetic reorganization of chromatin during CD8 + Teff differentiation in cooperation with RUNX3 and IRF4 (86).…”

Section: Multimodal Analysis Revealing Stat5 Regulation Of Adgre5mentioning

confidence: 98%

ADGRE5-centered Tsurv model in T cells recognizes responders to neoadjuvant cancer immunotherapy

Li,

Meng,

Cao

et al. 2024

Front. Immunol.

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BackgroundNeoadjuvant immunotherapy with anti-programmed death-1 (neo-antiPD1) has revolutionized perioperative methods for improvement of overall survival (OS), while approaches for major pathologic response patients’ (MPR) recognition along with methods for overcoming non-MPR resistance are still in urgent need.MethodsWe utilized and integrated publicly-available immune checkpoint inhibitors regimens (ICIs) single-cell (sc) data as the discovery datasets, and innovatively developed a cell-communication analysis pipeline, along with a VIPER-based-SCENIC process, to thoroughly dissect MPR-responding subsets. Besides, we further employed our own non-small cell lung cancer (NSCLC) ICIs cohort’s sc data for validation in-silico. Afterward, we resorted to ICIs-resistant murine models developed by us with multimodal investigation, including bulk-RNA-sequencing, Chip-sequencing and high-dimensional cytometry by time of flight (CYTOF) to consolidate our findings in-vivo. To comprehensively explore mechanisms, we adopted 3D ex-vivo hydrogel models for analysis. Furthermore, we constructed an ADGRE5-centered Tsurv model from our discovery dataset by machine learning (ML) algorithms for a wide range of tumor types (NSCLC, melanoma, urothelial cancer, etc.) and verified it in peripheral blood mononuclear cells (PBMCs) sc datasets.ResultsThrough a meta-analysis of multimodal sequential sc sequencing data from pre-ICIs and post-ICIs, we identified an MPR-expanding T cells meta-cluster (MPR-E) in the tumor microenvironment (TME), characterized by a stem-like CD8+ T cluster (survT) with STAT5-ADGRE5 axis enhancement compared to non-MPR or pre-ICIs TME. Through multi-omics analysis of murine TME, we further confirmed the existence of survT with silenced function and immune checkpoints (ICs) in MPR-E. After verification of the STAT5-ADGRE5 axis of survT in independent ICIs cohorts, an ADGRE5-centered Tsurv model was then developed through ML for identification of MPR patients pre-ICIs and post-ICIs, both in TME and PBMCs, which was further verified in pan-cancer immunotherapy cohorts. Mechanistically, we unveiled ICIs stimulated ADGRE5 upregulation in a STAT5-IL32 dependent manner in a 3D ex-vivo system (3D-HYGTIC) developed by us previously, which marked Tsurv with better survival flexibility, enhanced stemness and potential cytotoxicity within TME.ConclusionOur research provides insights into mechanisms underlying MPR in neo-antiPD1 and a well-performed model for the identification of non-MPR.

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Batf-mediated Epigenetic Control of Effector CD8+ T Cell Differentiation

Cited by 3 publications

References 116 publications

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

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

Epigenetics: An opportunity to shape innate and adaptive immune responses

ADGRE5-centered Tsurv model in T cells recognizes responders to neoadjuvant cancer immunotherapy

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