論文 - 柴田　淳史

Relative Biological Effectiveness of Carbon Ions for Head-and-Neck Squamous Cell Carcinomas According to Human Papillomavirus Status

Naoto Osu, Daijiro Kobayashi, Katsuyuki Shirai, Atsushi Musha, Hiro Sato, Yuka Hirota, Atsushi Shibata, Takahiro Oike, Tatsuya Ohno

Journal of Personalized Medicine （MDPI AG）  10 （ 3 ） 71 - 71 2020年07月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

Carbon-ion radiotherapy (CIRT) has strong antitumor effects and excellent dose conformity. In head-and-neck squamous cell carcinoma (HNSCC), human papillomavirus (HPV) status is a prognostic factor for photon radiotherapy outcomes. However, the effect of HPV status on the sensitivity of HNSCCs to carbon ions remains unclear. Here, we showed that the relative biological effectiveness (RBE) of carbon ions over X-rays was higher in HPV-negative cells than in HSGc-C5 cells, which are used for CIRT dose establishment, whereas the RBE in HPV-positive cells was modest. These data indicate that CIRT is more advantageous in HPV-negative than in HPV-positive HNSCCs.

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RNF8 promotes high linear energy transfer carbon-ion-induced DNA double-stranded break repair in serum-starved human cells

Nakako Izumi Nakajima, Motohiro Yamauchi, Sangeeta Kakoti, Liu Cuihua, Reona Kato, Tiara Bunga Mayang Permata, Moito Iijima, Hirohiko Yajima, Takaaki Yasuhara, Shigeru Yamada, Sumitaka Hasegawa, Atsushi Shibata

DNA Repair （Elsevier BV）  91-92   102872 - 102872 2020年07月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り,  ISSN  1568-7864

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DNA double-strand break end resection: a critical relay point for determining the pathway of repair and signaling

Yoko Katsuki, Penny A. Jeggo, Yuki Uchihara, Minoru Takata, Atsushi Shibata

Genome Instability & Disease （Springer Science and Business Media LLC）  1 （ 4 ） 155 - 171 2020年07月

査読有り

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UBC13-Mediated Ubiquitin Signaling Promotes Removal of Blocking Adducts from DNA Double-Strand Breaks

Remi Akagawa, Hai Thanh Trinh, Liton Kumar Saha, Masataka Tsuda, Kouji Hirota, Shintaro Yamada, Atsushi Shibata, Masato T. Kanemaki, Shinichiro Nakada, Shunichi Takeda, Hiroyuki Sasanuma

iScience （Elsevier BV）  23 （ 4 ） 101027 - 101027 2020年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2589-0042

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Chemical modifications and adducts at DNA double-strand break (DSB) ends must be cleaned before re-joining by non-homologous end-joining (NHEJ). MRE11 nuclease is essential for efficient removal of Topoisomerase II (TOP2)-DNA adducts from TOP2 poison-induced DSBs. However, mechanisms in MRE11 recruitment to DSB sites in G1 phase remain poorly understood. Here, we report that TOP2-DNA adducts are expeditiously removed through UBC13-mediated polyubiquitination, which promotes DSB resection in G2 phase. We found that this ubiquitin signaling is required for efficient recruitment of MRE11 onto DSB sites in G1 by facilitating localization of RAP80 and BRCA1 to DSB sites and complex formation between BRCA1 and MRE11 at DSB sites. UBC13 and MRE11 are dispensable for restriction-enzyme-induced “clean” DSBs repair but responsible for over 50% and 70% of NHEJ-dependent repair of γ-ray-induced “dirty” DSBs, respectively. In conclusion, ubiquitin signaling promotes nucleolytic removal of DSB blocking adducts by MRE11 before NHEJ.

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Canonical DNA non-homologous end-joining; capacity versus fidelity.

Atsushi Shibata, Penny A Jeggo

The British journal of radiology    20190966 - 20190966 2020年01月

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　概要を見る

The significance of canonical DNA non-homologous end-joining (c-NHEJ) for DNA double strand break (DSB) repair has increased from lower organisms to higher eukaryotes, and plays the predominant role in human cells. Ku, the c-NHEJ end-binding component, binds DSBs with high efficiency enabling c-NHEJ to be the first choice DSB repair pathway, although alternative pathways can ensue after regulated steps to remove Ku. Indeed, radiation-induced DSBs are repaired rapidly in human cells. However, an important question is the fidelity with which radiation-induced DSBs are repaired, which is essential for assessing any harmful impacts caused by radiation exposure. Indeed, is compromised fidelity a price we pay for high capacity repair. Two subpathways of c-NHEJ have been revealed; a fast process that does not require nucleases or significant chromatin changes and a slower process that necessitates resection factors, and potentially more significant chromatin changes at the DSB. Recent studies have also shown that DSBs within transcriptionally active regions are repaired by specialised mechanisms, and the response at such DSBs encompasses a process of transcriptional arrest. Here, we consider the limitations of c-NHEJ that might result in DSB misrepair. We consider the common IR-induced misrepair events and discuss how they might arise via the distinct subpathways of c-NHEJ.

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p53 deficiency augments nucleolar instability after ionizing irradiation.

Sangeeta Kakoti, Motohiro Yamauchi, Wenchao Gu, Reona Kato, Takaaki Yasuhara, Yoshihiko Hagiwara, Siddhartha Laskar, Takahiro Oike, Hiro Sato, Kathryn D Held, Takashi Nakano, Atsushi Shibata

Oncology reports （Spandidos publications）  42 （ 6 ） 2293 - 2302 2019年12月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

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Ribosomes are important cellular components that maintain cellular homeostasis through overall protein synthesis. The nucleolus is a prominent subnuclear structure that contains ribosomal DNA (rDNA) encoding ribosomal RNA (rRNA), an essential component of ribosomes. Despite the significant role of the rDNA‑rRNA‑ribosome axis in cellular homeostasis, the stability of rDNA in the context of the DNA damage response has not been fully investigated. In the present study, the number and morphological changes of nucleolin, a marker of the nucleolus, were examined following ionizing radiation (IR) in order to investigate the impact of DNA damage on nucleolar stability. An increase in the number of nucleoli per cell was found in HCT116 and U2OS cells following IR. Interestingly, the IR‑dependent increase in nucleolar fragmentation was enhanced by p53 deficiency. In addition, the morphological analysis revealed several distinct types of nucleolar fragmentation following IR. The pattern of nucleolar morphology differed between HCT116 and U2OS cells, and the p53 deficiency altered the pattern of nucleolar morphology. Finally, a significant decrease in rRNA synthesis was observed in HCT116 p53‑/‑ cells following IR, suggesting that severe nucleolar fragmentation downregulates rRNA transcription. The findings of the present study suggest that p53 plays a key role in protecting the transcriptional activity of rDNA in response to DNA damage.

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Analysis of nucleolus stability after ionizing irradiation(和訳中)

Kakoti Sangeeta, 萩原 慶彦, 佐藤 浩央, 尾池 貴洋, 中野 隆史, 柴田 淳史

日本放射線影響学会大会講演要旨集 （(一社)日本放射線影響学会）  62回   44 - 44 2019年11月

ISSN  1347-8680

イオン線照射後の核安定性に関する分析(Analysis of nucleolus stability after ionizing irradiation)

Kakoti Sangeeta, 萩原 慶彦, 佐藤 浩央, 尾池 貴洋, 中野 隆史, 柴田 淳史

日本放射線影響学会大会講演要旨集 （(一社)日本放射線影響学会）  62回   44 - 44 2019年11月

ISSN  1347-8680

Combination of Anti-Cancer Drugs with Molecular Chaperone Inhibitors.

Maxim Shevtsov, Gabriele Multhoff, Elena Mikhaylova, Atsushi Shibata, Irina Guzhova, Boris Margulis

International journal of molecular sciences 20 （ 21 ）  2019年10月

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Most molecular chaperones belonging to heat shock protein (HSP) families are known to protect cancer cells from pathologic, environmental and pharmacological stress factors and thereby can hamper anti-cancer therapies. In this review, we present data on inhibitors of the heat shock response (particularly mediated by the chaperones HSP90, HSP70, and HSP27) either as a single treatment or in combination with currently available anti-cancer therapeutic approaches. An overview of the current literature reveals that the co-administration of chaperone inhibitors and targeting drugs results in proteotoxic stress and violates the tumor cell physiology. An optimal drug combination should simultaneously target cytoprotective mechanisms and trigger the imbalance of the tumor cell physiology.

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Deep learning-assisted literature mining for in vitro radiosensitivity data.

Shuichiro Komatsu, Takahiro Oike, Yuka Komatsu, Yoshiki Kubota, Makoto Sakai, Toshiaki Matsui, Endang Nuryadi, Tiara Bunga Mayang Permata, Hiro Sato, Hidemasa Kawamura, Masahiko Okamoto, Takuya Kaminuma, Kazutoshi Murata, Naoko Okano, Yuka Hirota, Tatsuya Ohno, Jun-Ichi Saitoh, Atsushi Shibata, Takashi Nakano

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology （Elsevier）  139   87 - 93 2019年10月

共著, 査読有り

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BACKGROUND AND PURPOSE: Integrated analysis of existing radiosensitivity data obtained by the gold-standard clonogenic assay has the potential to improve our understanding of cancer cell radioresistance. However, extraction of radiosensitivity data from the literature is highly labor-intensive. To aid in this task, using deep convolutional neural networks (CNNs) and other computer technologies, we developed an analysis pipeline that extracts radiosensitivity data derived from clonogenic assays from the literature. MATERIALS AND METHODS: Three classifiers (C1-3) were developed to identify publications containing radiosensitivity data derived from clonogenic assays. C1 uses Faster Regions CNN with Inception Resnet v2 (fRCNN-IRv2), VGG-16, and Optical Character Recognition (OCR) to identify publications that contain semi-logarithmic graphs showing radiosensitivity data derived from clonogenic assays. C2 uses fRCNN-IRv2 and OCR to identify publications that contain bar graphs showing radiosensitivity data derived from clonogenic assays. C3 is a program that identifies publications containing keywords related to radiosensitivity data derived from clonogenic assays. A program (iSF2) was developed using Mask RCNN and OCR to extract surviving fraction after 2-Gy irradiation (SF2) as assessed by clonogenic assays, presented in semi-logarithmic graphs. The efficacy of C1-3 and iSF2 was tested using seven datasets (1805 and 222 publications in total, respectively). RESULTS: C1-3 yielded sensitivity of 91.2% ± 3.4% and specificity of 90.7% ± 3.6%. iSF2 returned SF2 values that were within 2.9% ± 2.6% of the SF2 values determined by radiation oncologists. CONCLUSION: Our analysis pipeline is potentially useful to acquire radiosensitivity data derived from clonogenic assays from the literature.

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FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy.

Narisa Dewi Maulany Darwis, Ankita Nachankar, Yasushi Sasaki, Toshiaki Matsui, Shin-Ei Noda, Kazutoshi Murata, Tomoaki Tamaki, Ken Ando, Noriyuki Okonogi, Shintaro Shiba, Daisuke Irie, Takuya Kaminuma, Takuya Kumazawa, Mai Anakura, Souichi Yamashita, Takashi Hirakawa, Sangeeta Kakoti, Yuka Hirota, Takashi Tokino, Akira Iwase, Tatsuya Ohno, Atsushi Shibata, Takahiro Oike, Takashi Nakano

International journal of molecular sciences （MDPI）  20 （ 18 ） 4563 2019年09月

研究論文（学術雑誌）, 共著, 査読有り

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Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.

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Robustness of Clonogenic Assays as a Biomarker for Cancer Cell Radiosensitivity.

Toshiaki Matsui, Endang Nuryadi, Shuichiro Komatsu, Yuka Hirota, Atsushi Shibata, Takahiro Oike, Takashi Nakano

International journal of molecular sciences （MDPI）  20 （ 17 ） 4148 2019年08月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

Photon radiation therapy is a major curative treatment for cancer. However, the lack of robust predictive biomarkers for radiosensitivity precludes personalized radiation therapy. Clonogenic assays are the gold standard method for measuring the radiosensitivity of cancer cells. Although a large number of publications describe the use of clonogenic assays to measure cancer cell radiosensitivity, the robustness of results from different studies is unclear. To address this, we conducted a comprehensive detailed literature search of 256 common cancer cell lines and identified the eight cell lines most-frequently examined for photon sensitivity using clonogenic assays. Survival endpoints and experimental parameters from all 620 relevant experiments were compiled and analyzed. We found that the coefficients of variation for SF2 (surviving fraction after 2 Gy irradiation) and for D10 (dose that yields a surviving fraction of 10%) were below 30% for all cell lines, indicating that SF2 and D10 have acceptable inter-assay precision. These data support further analysis of published data on clonogenic assays using SF2 and D10 as survival endpoints, which facilitates robust identification of biological profiles representative of cancer cell sensitivity to photons.

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Radiosensitivity Differences between EGFR Mutant and Wild-Type Lung Cancer Cells are Larger at Lower Doses

Mai Anakura, Ankita Nachankar, Daijiro Kobayashi, Napapat Amornwichet, Yuka Hirota, Atsushi Shibata, Takahiro Oike, Takashi Nakano

International Journal of Molecular Sciences （MDPI）  20 （ 15 ） 3635 2019年07月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

In the era of precision medicine, radiotherapy strategies should be determined based on genetic profiles that predict tumor radiosensitivity. Accordingly, pre-clinical research aimed at discovering clinically applicable genetic profiles is needed. However, how a given genetic profile affects cancer cell radiosensitivity is unclear. To address this issue, we performed a pilot in vitro study by utilizing EGFR mutational status as a model for genetic profile. Clonogenic assays of EGFR mutant (n = 6) and wild-type (n = 9) non-small cell lung carcinoma (NSCLC) cell lines were performed independently by two oncologists. Clonogenic survival parameters SF2, SF4, SF6, SF8, mean inactivation dose (MID), D10, D50, α, and β were obtained using the linear quadratic model. The differences in the clonogenic survival parameters between the EGFR mutant and wild-type cell lines were assessed using the Mann-Whitney U test. As a result, for both datasets, the p values for SF2, SF4, D50, α, and α/β were below 0.05, and those for SF2 were lowest. These data indicate that a genetic profile of NSCLC cell lines might be predictive for their radiation response; i.e., EGFR mutant cell lines might be more sensitive to low dose- and low fraction sized-irradiation.

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Base excision repair regulates PD-L1 expression in cancer cells.

Tiara Bunga Mayang Permata, Yoshihiko Hagiwara, Hiro Sato, Takaaki Yasuhara, Takahiro Oike, Soehartati Gondhowiardjo, Kathryn D Held, Takashi Nakano, Atsushi Shibata

Oncogene （Springer nature）  38 （ 23 ） 4452 - 4466 2019年06月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

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Programmed death-ligand 1 (PD-L1) is a key factor influencing cancer immunotherapy; however, the regulation of PD-L1 expression in cancer cells remains unclear, particularly regarding DNA damage, repair and its signalling. Herein, we demonstrate that oxidative DNA damage induced by exogenously applied hydrogen peroxide (H2O2) upregulates PD-L1 expression in cancer cells. Further, depletion of the base excision repair (BER) enzyme DNA glycosylase augments PD-L1 upregulation in response to H2O2. PD-L1 upregulation in BER-depleted cells requires ATR/Chk1 kinase activities, demonstrating that PD-L1 upregulation is mediated by DNA damage signalling. Further analysis of The Cancer Genome Atlas revealed that the expression of PD-L1 is negatively correlated with that of the BER/single-strand break repair (SSBR) and tumours with low BER/SSBR gene expression show high microsatellite instability and neoantigen production. Hence, these results suggest that PD-L1 expression is regulated in cancer cells via the DNA damage signalling and neoantigen-interferon-γ pathway under oxidative stress.

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Elucidation of the Mechanism Regulating Transcription Associated DNA Double Strand Break Repair and Its Pathway.

Atsushi Shibata, Takaaki Yasuhara

Impact （Science Impact Ltd）  2019 （ 3 ） 50 - 51 2019年03月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者, 査読有り

　概要を見る

The ability to repair breaks and mutations in DNA is essential for a cell's – and therefore organism's – survival. Breaks and other mutations arise naturally over time and are dealt with by the cell using several different pathways. Incorrect or non-existent DNA repair can lead directly to either cell death or the development of a cancerous cell. A break in double strand in the DNA is particularly serious. Dr Atsushi Shibata, a Principle Investigator and Senior Lecturer at Gunma University, Japan explains that the cell has two key ways to deal with this sort of break. 'These are homologous recombination repair (HRR) and non-homologous end-joining (NHEJ),' he says. 'HRR is the more accurate pathway, while NHEJ provides a quicker fix, but it has a risk of error under some circumstance.' This makes HRR perfectly suited to repairing important parts of the genome whilst NHEJ is better suited to less key regions.
The molecular mechanisms behind these repair pathways have been extensively studied. However, the question of how a particular pathway is selected over another in different situations is less well characterised, particularly in human normal cells as well as cancer cells. Uncovering the signalling pathways behind this choice the cell makes is both very important to our fundamental understanding of DNA repair and to its potential use in tackling cancer. Investigating these pathways Shibata is collaborating with Dr Takaaki Yasuhara from the University of Tokyo. They have revealed some of the inner workings behind the choice of repair pathway.
Previously, Shibata has shown that the NHEJ was the default choice for repairing DSBs, but that HRR is then selected if the re-joining does not occur properly. He has also shown a fundamental role of MRE11 nuclease in determining the type of repair that occurs at a DSB. Additionally, Shibata has shown the crucial role BRCA1 has in directing the repair of DSB towards the HRR pathway. In short, his work in the field is internationally recognised. 'These studies have contributed to the establishment of research basis for the recent discovery in the study of transcription-associated HRR,' observes Shibata.

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Clustered DNA double-strand break formation and the repair pathway following heavy-ion irradiation.

Yoshihiko Hagiwara, Takahiro Oike, Atsuko Niimi, Motohiro Yamauchi, Hiro Sato, Siripan Limsirichaikul, Kathryn D Held, Takashi Nakano, Atsushi Shibata

Journal of radiation research （Oxford University Press）  60 （ 1 ） 69 - 79 2019年01月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

　概要を見る

Photons, such as X- or γ-rays, induce DNA damage (distributed throughout the nucleus) as a result of low-density energy deposition. In contrast, particle irradiation with high linear energy transfer (LET) deposits high-density energy along the particle track. High-LET heavy-ion irradiation generates a greater number and more complex critical chromosomal aberrations, such as dicentrics and translocations, compared with X-ray or γ irradiation. In addition, the formation of >1000 bp deletions, which is rarely observed after X-ray irradiation, has been identified following high-LET heavy-ion irradiation. Previously, these chromosomal aberrations have been thought to be the result of misrepair of complex DNA lesions, defined as DNA damage through DNA double-strand breaks (DSBs) and single-strand breaks as well as base damage within 1-2 helical turns (<3-4 nm). However, because the scale of complex DNA lesions is less than a few nanometers, the large-scale chromosomal aberrations at a micrometer level cannot be simply explained by complex DNA lesions. Recently, we have demonstrated the existence of clustered DSBs along the particle track through the use of super-resolution microscopy. Furthermore, we have visualized high-level and frequent formation of DSBs at the chromosomal boundary following high-LET heavy-ion irradiation. In this review, we summarize the latest findings regarding the hallmarks of DNA damage structure and the repair pathway following heavy-ion irradiation. Furthermore, we discuss the mechanism through which high-LET heavy-ion irradiation may induce dicentrics, translocations and large deletions.

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A historical reflection on our understanding of radiation-induced DNA double strand break repair in somatic mammalian cells; interfacing the past with the present

Atsushi Shibata, Penny Jeggo

International Journal of Radiation Biology 2019年

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Regulation of PD-L1 expression in response to DNA damage in cancer cells: Implications for precision medicine

Hiro Sato, Penny A. Jeggo, Atsushi Shibata, Sangeeta Kakoti, Motohiro Yamauchi, Wenchao Gu, Reona Kato, Takaaki Yasuhara, Yoshihiko Hagiwara, Siddhartha Laskar, Takahiro Oike, Hiro Sato, Kathryn D. Held, Takashi Nakano, Atsushi Shibata, Corresponding author

Cancer Science 2019年

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Novel Approaches to Improve the Efficacy of Immuno-Radiotherapy.

Maxim Shevtsov, Hiro Sato, Gabriele Multhoff, Atsushi Shibata

Frontiers in oncology 9   156 - 156 2019年

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　概要を見る

Radiotherapy (RT) has been applied for decades as a treatment modality in the management of various types of cancer. Ionizing radiation induces tumor cell death, which in turn can either elicit protective anti-tumor immune responses or immunosuppression in the tumor micromilieu that contributes to local tumor recurrence. Immunosuppression is frequently accompanied by the attraction of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), M2 tumor-associated macrophages (TAMs), T regulatory cells (Tregs), N2 neutrophils, and by the release of immunosuppressive cytokines (TGF-β, IL-10) and chemokines. Immune checkpoint pathways, particularly of the PD-1/PD-L1 axis, have been determined as key regulators of cancer immune escape. While IFN-dependent upregulation of PD-L1 has been extensively investigated, up-to-date studies indicated the importance of DNA damage signaling in the regulation of PD-L1 expression following RT. DNA damage dependent PD-L1 expression is upregulated by ATM/ATR/Chk1 kinase activities and cGAS/STING-dependent pathway, proving the role of DNA damage signaling in PD-L1 induced expression. Checkpoint blockade immunotherapies (i.e., application of anti-PD-1 and anti-PD-L1 antibodies) combined with RT were shown to significantly improve the objective response rates in therapy of various primary and metastatic malignancies. Further improvements in the therapeutic potential of RT are based on combinations of RT with other immunotherapeutic approaches including vaccines, cytokines and cytokine inducers, and an adoptive immune cell transfer (DCs, NK cells, T cells). In the current review we provide immunological rationale for a combination of RT with various immunotherapies as well as analysis of the emerging preclinical evidences for these therapies.

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相同組換え修復への経路切り替えを促進する時空間的53BP1動態制御機構

磯野 真由, 萩原 慶彦, 佐藤 浩央, 尾池 貴洋, 西 良太郎, 中田 慎一郎, 中野 隆史, 鈴木 啓司, 柴田 淳史

日本放射線影響学会大会講演要旨集 （(一社)日本放射線影響学会）  61回   51 - 51 2018年11月

ISSN  1347-8680