Transposable elements potentiate radiotherapy-induced cellular immune reactions via RIG-I-mediated virus-sensing pathways

Abstract

Radiotherapy (RT) plus immunotherapy is a promising modality; however, the therapeutic effects are insufficient, and the molecular mechanism requires clarification to further develop combination therapies. Here, we found that the RNA virus sensor pathway dominantly regulates the cellular immune response in NSCLC and ESCC cell lines. Notably, transposable elements (TEs), especially long terminal repeats (LTRs), functioned as key ligands for the RNA virus sensor RIG-I, and the mTOR–LTR–RIG-I axis induced the cellular immune response and dendritic cell and macrophage infiltration after irradiation. Moreover, RIG-I-dependent immune activation was observed in ESCC patient tissue. scRNA sequencing and spatial transcriptome analysis revealed that radiotherapy induced the expression of LTRs, and the RNA virus sensor pathway in immune and cancer cells; this pathway was also found to mediate tumour conversion to an immunological hot state. Here, we report the upstream and ligand of the RNA virus sensor pathway functions in irradiated cancer tissues.

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

“…Although the IFN-β response observed after irradiation is largely mediated by the activation of cytoplasmic dsDNA sensors, proton-irradiated organoids display a higher increase of TE expression, accompanied by an accumulation of cytoplasmic dsRNA and upregulation of the dsRNA sensor RIG-I. Elevated levels of TEs, dsRNA, and RIG-I have been shown to enhance the immune response of cancer cells following irradiation 49 . However, our study reveals that this phenomenon extends beyond tumors, as irradiated non-tumor cells also express these immune-enhancing elements.…”

Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities

“…The RLR family members, RIG-I and MDA5, functioning as intracellular pattern recognition receptors, are gaining prominence as potential therapeutic targets in cancer due to their capacity to engage with mislocalized mtRNA and other innate RNAs, thus triggering potent immune responses [ 187 ]. Emerging research has highlighted the role of the mTOR-LTR-RIG-I axis in various cancers in driving cellular immune responses and facilitating the infiltration of dendritic cells and macrophages [ 188 ]. Notably, the overexpression of RIG-I in peritoneal macrophages has been demonstrated to facilitate the transition from M2 to M1 macrophage polarization, thereby impeding tumor advancement [ 189 ].…”

Radiotherapy and immunology

“…Deletion of RIG-I in cancer cells renders them resistant to IR and chemotherapy ( Ranoa et al, 2016 ). IR is reported to induce long terminal repeats (LTRs), which are key ligands for the RNA virus sensor RIG-I ( Du et al, 2023 ). The activated mTOR–LTR–RIG-I axis induces cellular immune response by dramatically increasing inflammatory cytokine and chemokine production, potentially enhancing DC and macrophage infiltration after irradiation.…”