研究者詳細 - 日野原　邦彦

BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state

Heterogeneity and transcriptional drivers of triple-negative breast cancer 査読有り国際共著

Jovanović B, Temko D, Stevens LE, Seehawer M, Fassl A, Murphy K, Anand J, Garza K, Gulvady A, Qiu X, Harper NW, Daniels VW, Xiao-Yun H, Ge JY, Alečković M, Pyrdol J, Hinohara K, Egri SB, Papanastasiou M, Vadhi R, Font-Tello A, Witwicki R, Peluffo G, Trinh A, Shu S, Diciaccio B, Ekram MB, Subedee A, Herbert ZT, Wucherpfennig KW, Letai AG, Jaffe JD, Sicinski P, Brown M, Dillon D, Long HW, Michor F, Polyak K.

Cell Rep. 42 巻 ( 12 ) 頁： 113564 - 113564 2023年12月

Xiao, MR; Kondo, S; Nomura, M; Kato, S; Nishimura, K; Zang, WJ; Zhang, YF; Akashi, T; Viny, A; Shigehiro, T; Ikawa, T; Yamazaki, H; Fukumoto, M; Tanaka, A; Hayashi, Y; Koike, Y; Aoyama, Y; Ito, H; Nishikawa, H; Kitamura, T; Kanai, A; Yokoyama, A; Fujiwara, T; Goyama, S; Noguchi, H; Lee, SC; Toyoda, A; Hinohara, K; Abdel-Wahab, O; Inoue, D

NATURE COMMUNICATIONS 14 巻 ( 1 ) 頁： 8372 2023年12月

記述言語：英語出版者・発行元：Nature Communications

ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.

DOI： 10.1038/s41467-023-44081-6

The cancer epigenome: Non-cell autonomous player in tumor immunity

Kato, S; Maeda, Y; Sugiyama, D; Watanabe, K; Nishikawa, H; Hinohara, K

CANCER SCIENCE 114 巻 ( 3 ) 頁： 730 - 740 2023年3月

記述言語：英語出版者・発行元：Cancer Science

Dysregulation of the tumor-intrinsic epigenetic circuit is a key driver event for the development of cancer. Accumulating evidence suggests that epigenetic and/or genetic drivers stimulate intrinsic oncogenic pathways as well as extrinsic factors that modulate the immune system. These modulations indeed shape the tumor microenvironment (TME), allowing pro-oncogenic factors to become oncogenic, thereby contributing to cancer development and progression. Here we review the epigenetic dysregulation arising in cancer cells that disseminates throughout the TME and beyond. Recent CRISPR screening has elucidated key epigenetic drivers that play important roles in the proliferation of cancer cells (intrinsic) and inhibition of antitumor immunity (extrinsic), which lead to the development and progression of cancer. These epigenetic players can serve as promising targets for cancer therapy as a dual (two-in-one)-targeted approach. Considering the interplay between cancer and the immune system as a key determinant of immunotherapy, we discuss a novel lineage-tracing technology that enables longitudinal monitoring of cancer and immune phenotypic heterogeneity and fate paths during cancer development, progression, and therapeutic interventions.

DOI： 10.1111/cas.15681

Significance of regulatory T cells in cancer immunology and immunotherapy

Sugiyama, D; Hinohara, K; Nishikawa, H

EXPERIMENTAL DERMATOLOGY 32 巻 ( 3 ) 頁： 256 - 263 2023年3月

記述言語：英語出版者・発行元：Experimental Dermatology

Immunosuppression in the tumour microenvironment (TME) attenuates antitumor immunity, consequently hindering protective immunosurveillance and preventing effective antitumor immunity induced by cancer immunotherapy. Multiple mechanisms including immune checkpoint molecules, such as CTLA-4, PD-1, and LAG-3, and immunosuppressive cells are involved in the immunosuppression in the TME. Regulatory T (Treg) cells, a population of immunosuppressive cells, play an important role in inhibiting antitumor immunity. Therefore, Treg cells in the TME correlate with an unfavourable prognosis in various cancer types. Thus, Treg cell is considered to become a promising target for cancer immunotherapy. Elucidating Treg cell functions in cancer patients is therefore crucial for developing optimal Treg cell-targeted immunotherapy. Here, we describe Treg cell functions and phenotypes in the TME from the perspective of Treg cell-targeted immunotherapy.

DOI： 10.1111/exd.14721

CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer

Tsujino, T; Takai, T; Hinohara, K; Gui, F; Tsutsumi, T; Bai, X; Miao, CK; Feng, C; Gui, B; Sztupinszki, Z; Simoneau, A; Xie, N; Fazli, L; Dong, XS; Azuma, H; Choudhury, AD; Mouw, KW; Szallasi, Z; Zou, L; Kibel, AS; Jia, L

NATURE COMMUNICATIONS 14 巻 ( 1 ) 頁： 252 2023年1月

記述言語：英語出版者・発行元：Nature Communications

Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed (up to 14%) in prostate cancer, renders cells hypersensitive to PARP inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer.

DOI： 10.1038/s41467-023-35880-y

A bifurcation concept for B-lymphoid/plasmacytoid dendritic cells with largely fluctuating transcriptome dynamics

Nagaharu, K; Kojima, Y; Hirose, H; Minoura, K; Hinohara, K; Minami, H; Kageyama, Y; Sugimoto, Y; Masuya, M; Nii, S; Seki, M; Suzuki, Y; Tawara, I; Shimamura, T; Katayama, N; Nishikawa, H; Ohishi, K

CELL REPORTS 40 巻 ( 9 ) 頁： 111260 2022年8月

記述言語：英語出版者・発行元：Cell Reports

Hematopoiesis was considered a hierarchical stepwise process but was revised to a continuous process following single-cell RNA sequencing. However, the uncertainty or fluctuation of single-cell transcriptome dynamics during differentiation was not considered, and the dendritic cell (DC) pathway in the lymphoid context remains unclear. Here, we identify human B-plasmacytoid DC (pDC) bifurcation as large fluctuating transcriptome dynamics in the putative B/NK progenitor region by dry and wet methods. By converting splicing kinetics into diffusion dynamics in a deep generative model, our original computational methodology reveals strong fluctuation at B/pDC bifurcation in IL-7Rα+ regions, and LFA-1 fluctuates positively in the pDC direction at the bifurcation. These expectancies are validated by the presence of B/pDC progenitors in the IL-7Rα+ fraction and preferential expression of LFA-1 in pDC-biased progenitors with a niche-like culture system. We provide a model of fluctuation-based differentiation, which reconciles continuous and discrete models and is applicable to other developmental systems.

DOI： 10.1016/j.celrep.2022.111260

Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal

Isoyama, S; Mori, S; Sugiyama, D; Kojima, Y; Tada, Y; Shitara, K; Hinohara, K; Dan, S; Nishikawa, H

JOURNAL FOR IMMUNOTHERAPY OF CANCER 9 巻 ( 8 ) 2021年

記述言語：英語出版者・発行元：Journal for ImmunoTherapy of Cancer

Background Immune checkpoint blockade (ICB) induces durable clinical responses in patients with various types of cancer. However, its limited clinical efficacy requires the development of better approaches. In addition to immune checkpoint molecules, tumor-infiltrating immunosuppressive cells including regulatory T cells (Tregs) play crucial roles in the immune suppressive tumor microenvironment. While phosphatidylinositol 3-kinase (PI3K) inhibition as a Treg-targeted treatment has been implicated in animal models, its effects on human Tregs and on the potential impairment of effector T cells are required to be clarified for successful cancer immunotherapy. Methods The impact of a selective-PI3K inhibitor ZSTK474 with or without anti-programmed cell death 1 (PD-1) monoclonal antibody on Tregs and CD8 + T cells were examined with in vivo animal models and in vitro experiments with antigen specific and non-specific fashions using peripheral blood from healthy individuals and cancer patients. Phenotypes and functions of Tregs and effector T cells were examined with comprehensive gene and protein expression assays. Results Improved antitumor effects by the PI3K inhibitor in combination with ICB, particularly PD-1 blockade, were observed in mice and humans. Although administration of the PI3K inhibitor at higher doses impaired activation of CD8 + T cells as well as Tregs, the optimization (doses and timing) of this combination treatment selectively decreased intratumoral Tregs, resulting in increased tumor antigen-specific CD8 + T cells in the treated mice. Moreover, on the administration of the PI3K inhibitor with the optimal dose for selectively deleting Tregs, PI3K signaling was inhibited not only in Tregs but also in activated CD8 + T cells, leading to the enhanced generation of tumor antigen-specific memory CD8 + T cells which contributed to durable antitumor immunity. These opposing outcomes between Tregs and CD8 + T cells were attributed to the high degree of dependence on T cell signaling in the former but not in the latter. Conclusions PI3K inhibitor in the combination with ICB with the optimized protocol fine-tuned T cell activation signaling for antitumor immunity via decreasing Tregs and optimizing memory CD8 + T cell responses, illustrating a promising combination therapy.

DOI： 10.1136/jitc-2020-002279