bims-iorami Biomed News
on Ionising Radiation and Mitochondria
Issue of 2023–11–05
seven papers selected by
Chenxiao Yu, Soochow University
  1. Cytosolic DNA accumulation promotes breast cancer immunogenicity via a STING-independent pathway.
  2. GAS-STING: a classical DNA recognition pathways to tumor therapy.
  3. Innate immunity: Looking beyond T-cells in radiation and immunotherapy combinations.
  4. Insights on the radiation-induced adaptive response at the cellular level and its implications in cancer therapy.
  5. Radiation Dermatitis and Pneumonitis in Patients Irradiated for Breast Cancer.
  6. Mitochondrial complexome and import network.
  7. RNA N6-methyladenosine modification-based biomarkers for absorbed ionizing radiation dose estimation.
  1. J Immunother Cancer. 2023 Oct;pii: e007560. [Epub ahead of print]11(10):
    Cytosolic DNA accumulation promotes breast cancer immunogenicity via a STING-independent pathway.
    Jing Zhang, Hui Dai, Lei Huo, Jared K Burks, Daniel J McGrail, Shiaw-Yih Lin.
       BACKGROUND: Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, ICB alone has demonstrated only benefit in a small subset of patients with breast cancer. Recent studies have shown that agents targeting DNA damage response improve the efficacy of ICB and promote cytosolic DNA accumulation. However, recent clinical trials have shown that these agents are associated with hematological toxicities. More effective therapeutic strategies are urgently needed.
    METHODS: Primary triple negative breast cancer tumors were stained for cytosolic single-stranded DNA (ssDNA) using multiplex immunohistochemical staining. To increase cytosolic ssDNA, we genetically silenced TREX1. The role of tumor cytosolic ssDNA in promoting tumor immunogenicity and antitumor immune response was evaluated using murine breast cancer models.
    RESULTS: We found the tumorous cytosolic ssDNA is associated with tumor-infiltrating lymphocyte in patients with triple negative breast cancer. TREX1 deficiency triggered a STING-independent innate immune response via DDX3X. Cytosolic ssDNA accumulation in tumors due to TREX1 deletion is sufficient to drastically improve the efficacy of ICB. We further identified a cytosolic ssDNA inducer CEP-701, which sensitized breast tumors to ICB without the toxicities associated with inhibiting DNA damage response.
    CONCLUSIONS: This work demonstrated that cytosolic ssDNA accumulation promotes breast cancer immunogenicity and may be a novel therapeutic strategy to improve the efficacy of ICB with minimal toxicities.
    Keywords:  breast neoplasms; immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2023-007560
  2. Front Immunol. 2023 ;14 1200245
    GAS-STING: a classical DNA recognition pathways to tumor therapy.
    Xinrui Wang, Meijia Lin, Liping Zhu, Zhoujie Ye.
      Cyclic GMP-AMP synthetase (cGAS), recognized as the primary DNA sensor within cells, possesses the capability to identify foreign DNA molecules along with free DNA fragments. This identification process facilitates the production of type I IFNs through the activator of the interferon gene (STING) which induces the phosphorylation of downstream transcription factors. This action characterizes the most archetypal biological functionality of the cGAS-STING pathway. When treated with anti-tumor agents, cells experience DNA damage that triggers activation of the cGAS-STING pathway, culminating in the expression of type I IFNs and associated downstream interferon-stimulated genes. cGAS-STING is one of the important innate immune pathways,the role of type I IFNs in the articulation between innate immunity and T-cell antitumour immunity.type I IFNs promote the recruitment and activation of inflammatory cells (including NK cells) at the tumor site.Type I IFNs also can promote the activation and maturation of dendritic cel(DC), improve the antigen presentation of CD4+T lymphocytes, and enhance the cross-presentation of CD8+T lymphocytes to upregulating anti-tumor responses. This review discussed the cGAS-STING signaling and its mechanism and biological function in traditional tumor therapy and immunotherapy.
    Keywords:  DNA damage; cGAS-STING pathway; immune checkpoint inhibitor therapy; tumor immunotherapy; type I IFNs
    DOI:  https://doi.org/10.3389/fimmu.2023.1200245
  3. Neoplasia. 2023 Oct 30. pii: S1476-5586(23)00064-7. [Epub ahead of print]46 100940
    Innate immunity: Looking beyond T-cells in radiation and immunotherapy combinations.
    R A McMahon, C D'Souza, P J Neeson, S Siva.
      Radiation therapy is an established and effective anti-cancer treatment modality. Extensive pre-clinical experimentation has demonstrated that the pro-inflammatory properties of irradiation may be synergistic with checkpoint immunotherapy. Radiation induces double-stranded DNA breaks (dsDNA). Sensing of the dsDNA activates the cGAS/STING pathway, producing Type 1 interferons essential to recruiting antigen-presenting cells (APCs). Radiation promotes cytotoxic CD8 T-cell recruitment by releasing tumour-associated antigens captured and cross-presented by surveying antigen-presenting cells. Radiation-induced vascular normalisation may further promote T-cell trafficking and drug delivery. Radiation is also immunosuppressive. Recruitment of regulatory T cells (Tregs) and innate cells such as myeloid-derived suppressive cells (m-MDSCs) all counteract the immunostimulatory properties of radiation. Many innate immune cell types operate at the interface of the adaptive immune response. Innate immune cells, such as m-MDSCs, can exert their immunosuppressive effects by expressing immune checkpoints such as PD-L1, further highlighting the potential of combined radiation and checkpoint immunotherapy. Several early-phase clinical studies investigating the combination of radiation and immunotherapy have been disappointing. A greater appreciation of radiotherapy's impact on the innate immune system is essential to optimise radioimmunotherapy combinations. This review will summarise the impact of radiotherapy on crucial cells of the innate immune system and vital immunosuppressive cytokines.
    Keywords:  Immune system; Immunotherapy; Innate; Radiation; Radiotherapy
    DOI:  https://doi.org/10.1016/j.neo.2023.100940
  4. Cytogenet Genome Res. 2023 Oct 31.
    Insights on the radiation-induced adaptive response at the cellular level and its implications in cancer therapy.
    Aishwarya Thathamangalam Ananthanarayanan, Venkateswarlu Raavi, Satish Srinivas Kondaveeti, Ilangovan Ramachandran, Venkatachalam Perumal.
       BACKGROUND: Development of resistance upon exposure to small doses of ionizing radiation followed by higher doses is known as radiation-induced adaptive response (RIAR). Traditionally, the induction of the RIAR phenomenon at the cellular level has been examined in cell lines, animal models, and epidemiological studies where people live in high natural background radiation.
    SUMMARY: The primary intention of the earlier studies was to corroborate the existence of RIAR and the mechanism involved in mediating the response surveyed by exposure to a low dose of radiation (<500 mGy) as priming dose towards the radiation protection point of view. However, the investigation has shifted the focus to understand the relevance of this phenomenon at clinically relevant set-ups (high doses in the order of Gy) and can be exploited during radiotherapy as RIAR is considered a mechanism for the development of radioresistance. Although the knowledge of molecular mechanisms at the cellular level has evolved significantly in multi-fractionated radiotherapy regimes, its relevance in developing radioresistance at low doses remains elusive. The authors recapitulate the existing knowledge on RIAR at cellular levels, specifically after low-dose exposure as an adaptive dose, and discussed its potential implications in clinical radiotherapy outcomes.
    KEY MESSAGES: Recent studies contributed to understand the signaling molecules, pathways, and inhibitors to mitigate RIAR-mediated radiation resistance and persistent radio-tolerance at the cellular level. Monitoring the disease progression in tumor samples or liquid biopsies before, during, and after therapy with suitable biomarkers has been proposed as a strategy to translate the phenomena into clinical scenario.
    DOI:  https://doi.org/10.1159/000534500
  5. In Vivo. 2023 Nov-Dec;37(6):37(6): 2654-2661
    Radiation Dermatitis and Pneumonitis in Patients Irradiated for Breast Cancer.
    Marie C Eggert, Nathan Y Yu, Dirk Rades.
       BACKGROUND/AIM: Adjuvant radiotherapy (RT) for breast cancer can be associated with acute dermatitis (ARD) and pneumonitis (RP). Prevalence and risk factors were characterized.
    PATIENTS AND METHODS: This study included 489 breast cancer patients receiving adjuvant RT with conventional fractionation (CF) ± sequential or simultaneous integrated boost, or hypo-fractionation ± sequential boost. RT-regimen and 15 characteristics were investigated for grade ≥2 ARD and RP.
    RESULTS: Prevalence of grade ≥2 ARD and RP was 25.3% and 2.5%, respectively. On univariate analyses, ARD was significantly associated with CF and radiation boost (p<0.0001), age ≤60 years (p=0.008), Ki-67 ≥15% (p=0.012), and systemic treatment (p=0.002). On multivariate analysis, RT-regimen (p<0.0001) and age (p=0.009) were associated with ARD. Chronic inflammatory disease was significantly associated with RP on univariate (p=0.007) and multivariate (p=0.016) analyses.
    CONCLUSION: Risk factors for grade ≥2 ARD and RP were determined that may help identify patients who require closer monitoring during and after RT.
    Keywords:  Breast cancer; acute dermatitis; adjuvant radiotherapy; pneumonitis; prevalence; risk factors
    DOI:  https://doi.org/10.21873/invivo.13374
  6. Trends Cell Biol. 2023 Oct 30. pii: S0962-8924(23)00208-8. [Epub ahead of print]
    Mitochondrial complexome and import network.
    Fabian den Brave, Uwe Schulte, Bernd Fakler, Nikolaus Pfanner, Thomas Becker.
      Mitochondria perform crucial functions in cellular metabolism, protein and lipid biogenesis, quality control, and signaling. The systematic analysis of protein complexes and interaction networks provided exciting insights into the structural and functional organization of mitochondria. Most mitochondrial proteins do not act as independent units, but are interconnected by stable or dynamic protein-protein interactions. Protein translocases are responsible for importing precursor proteins into mitochondria and form central elements of several protein interaction networks. These networks include molecular chaperones and quality control factors, metabolite channels and respiratory chain complexes, and membrane and organellar contact sites. Protein translocases link the distinct networks into an overarching network, the mitochondrial import network (MitimNet), to coordinate biogenesis, membrane organization and function of mitochondria.
    Keywords:  cell organelles; energetics; metabolism; mitochondria; morphology; protein assembly; protein networks; protein sorting
    DOI:  https://doi.org/10.1016/j.tcb.2023.10.004
  7. Nat Commun. 2023 Oct 30. 14(1): 6912
    RNA N6-methyladenosine modification-based biomarkers for absorbed ionizing radiation dose estimation.
    Hongxia Chen, Xi Zhao, Wei Yang, Qi Zhang, Rongjiao Hao, Siao Jiang, Huihui Han, Zuyin Yu, Shuang Xing, Changjiang Feng, Qianqian Wang, Hao Lu, Yuanfeng Li, Cheng Quan, Yiming Lu, Gangqiao Zhou.
      Radiation triage and biological dosimetry are critical for the medical management of massive potentially exposed individuals following radiological accidents. Here, we performed a genome-wide screening of radiation-responding mRNAs, whose N6-methyladenosine (m6A) levels showed significant alteration after acute irradiation. The m6A levels of three genes, Ncoa4, Ate1 and Fgf22, in peripheral blood mononuclear cells (PBMCs) of mice showed excellent dose-response relationships and could serve as biomarkers of radiation exposure. Especially, the RNA m6A of Ncoa4 maintained a high level as long as 28 days after irradiation. We demonstrated its responsive specificity to radiation, conservation across the mice, monkeys and humans, and the dose-response relationship in PBMCs from cancer patients receiving radiation therapy. Finally, NOCA4 m6A-based biodosimetric models were constructed for estimating absorbed radiation doses in mice or humans. Collectively, this study demonstrated the potential feasibility of RNA m6A in radiation accidents management and clinical applications.
    DOI:  https://doi.org/10.1038/s41467-023-42665-w
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