bims-iorami Biomed News
on Ionising Radiation and Mitochondria
Issue of 2023‒12‒31
two papers selected by
Chenxiao Yu, Soochow University



  1. Front Immunol. 2023 ;14 1235936
      Circulating monocytes are important players of the inflammatory response to ionizing radiation (IR). These IR-resistant immune cells migrate to radiation-damaged tissues and differentiate into macrophages that phagocytize dying cells, but also facilitate inflammation. Besides the effect of damage-associated molecular patterns, released from irradiated tissues, the inflammatory activation of monocytes and macrophages is largely dependent on IR-induced DNA damage and aberrant transcriptional activity, which may facilitate expression of type I interferons (IFN-I) and numerous inflammation-related genes. We analyzed the accumulation of dsRNA, dsDNA fragments, and RNA:DNA hybrids in the context of induction of RNA-triggered MAVS-mediated and DNA-triggered STING-mediated signaling pathways, in primary human monocytes and a monocytic cell line, THP1, in response to various doses of gamma IR. We found that exposure to lower doses (<7.5 Gy) led to the accumulation of dsRNA, along with dsDNA and RNA:DNA hybrids and activated both MAVS and STING pathway-induced gene expression and signaling activity of IFN-I. Higher doses of IR resulted in the reduced dsRNA level, degradation of RNA-sensing mediators involved in MAVS signaling and coincided with an increased accumulation of dsDNA and RNA:DNA hybrids that correlated with elevated STING signaling and NF-κB-dependent gene expression. While both pathways activate IFN-I expression, using MAVS- and STING-knockout THP1 cells, we identified differences in the spectra of interferon-stimulated genes (ISGs) that are associated with each specific signaling pathway and outlined a large group of STING signaling-associated genes. Using the RNAi technique, we found that increasing the dose of IR activates STING signaling through the DNA sensor cGAS, along with suppression of the DDX41 helicase, which is known to reduce the accumulation of RNA:DNA hybrids and thereby limit cGAS/STING signaling activity. Together, these results indicate that depending on the applied dose, IR leads to the activation of either dsRNA-induced MAVS signaling, which predominantly leads to the expression of both pro- and anti-inflammatory markers, or dsDNA-induced STING signaling that contributes to pro-inflammatory activation of the cells. While RNA:DNA hybrids boost both MAVS- and STING-mediated signaling pathways, these structures being accumulated upon high IR doses promote type I interferon expression and appear to be potent enhancers of radiation dose-dependent pro-inflammatory activation of monocytes.
    Keywords:  MAVS; RIG-I-like receptors (RLRs); RNA:DNA hybrids; gamma radiation; macrophages; melanoma differentiation-associated protein 5 (MDA-5); monocytes; stimulator of interferon genes (STING)
    DOI:  https://doi.org/10.3389/fimmu.2023.1235936
  2. Int J Radiat Oncol Biol Phys. 2023 Dec 26. pii: S0360-3016(23)08252-4. [Epub ahead of print]
      INTRODUCTION: Larger tumors are underrepresented in most prospective trials on stereotactic body radiation therapy (SBRT) for inoperable non-small cell lung cancer (NSCLC). We performed this phase I trial to specifically study the maximum tolerated dose (MTD) of SBRT for NSCLC >3cm.METHODS: A 3+3 dose escalation design (cohort A) with an expansion cohort at the MTD (cohort B) was used. Patients with inoperable NSCLC >3cm (T2-4) were eligible. Select ipsilateral hilar and single station mediastinal nodes were permitted. The initial SBRT dose was 40 Gy in 5 fractions, with planned escalation to 50 and 60 Gy in 5 fractions. Adjuvant chemotherapy was mandatory for cohort A and optional for cohort B, but no patients in cohort B received chemotherapy. The primary endpoint was SBRT-related acute G4+ or persistent G3 toxicities (CTCAE v4.03). Secondary endpoints included local failure (LF), distant-metastases, disease progression and overall survival (OS).
    RESULTS: Median age was 80 years; tumor size was >3cm ≤5cm in 20 (59%) and >5cm in 14 (41%) patients. In cohort A (n=9), 3 patients treated to 50 Gy experienced G3 radiation pneumonitis (RP), thus defining the MTD. In the larger dose expansion cohort B (n=25), no RT-related G4+ toxicities and no G3 RP occurred; only 2 patients experienced G2 RP. The 2-year cumulative incidence of LF was 20.2%, distant failure was 34.7%, and disease progression was 54.4%. Two-year OS was 53%. A biologically effective dose <100 Gy was associated with higher LF (p=0.006); advanced stage and higher neutrophil/lymphocyte ratio (NLR) were associated with greater disease progression (both p=0.004).
    CONCLUSIONS: 50 Gy in 5 fraSabsctions is the MTD for SBRT to tumors >3cm. A higher BED is associated with less local failures even in larger tumors. Cohort B appears to have had less toxicity, possibly due to the omission of chemotherapy.
    TRIAL REGISTRATION: Clinicaltrials.gov: xxx.
    DOI:  https://doi.org/10.1016/j.ijrobp.2023.12.018