Low-dose photon irradiation induces invasiveness through the SDF-1α/CXCR4 pathway in malignant mesothelioma cells

Yamauchi, Yoshikane; Safi, Seyer; Orschiedt, Lena; Gardyan, Adriane; Brons, Stephan; Nicolay, Nils H.; Huber, Peter E.; Eichhorn, Martin; Dienemann, Hendrik; Herth, Felix J.F.; Weber, Klaus-Josef; Debus, Jürgen; Hoffmann, Hans; Rieken, Stefan

doi:10.18632/oncotarget.19134

Cited by 6 publications

(4 citation statements)

References 43 publications

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“…Similarly, Feig et al could restore the antitumour effects of antibody-based checkpoint inhibitors in a murine PDA model, when applied subsequently to prior administration of AMD3100 52 . In our study we could not determine any changes in the cell surface expression level of CXCR4 on PDA30364/OVA cells in response to irradiation with single doses from 1 to 10 Gy, which differs from results reported for mesothelioma cells 53 .…”

Section: Discussioncontrasting

confidence: 99%

Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line

Schröter

Hartmann

Osen

et al. 2020

Sci Rep

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Pancreatic ductal adenocarcinoma (PDA) is highlighted by resistance to radiotherapy with the possible exception of hypofractionated irradiation. As single photon doses were reported to increase immunogenicity, we investigated dose-dependent irradiation effects on clonogenic survival, expression of immunologically relevant cell surface molecules and susceptibility to cytotoxic T cell (CTL) mediated killing using a murine PDA cell line. Clonogenicity decreased in a dose-responsive manner showing enhanced radioresistance at single photon doses below 5 Gy. Cell cycle analysis revealed a predominant G2/M arrest, being most pronounced 12 h after irradiation. Polyploidy increased in a dose-and timedependent manner reaching a maximum frequency 60 h following irradiation with 10 Gy. Irradiation increased surface expression of MHC class I molecules and of immunological checkpoint molecules PDL-1 and CD73, especially at doses ≥ 5 Gy, but not of MHC class II molecules and CXCR4 receptors. Cytotoxicity assays revealed increased CTL lysis of PDA cells at doses ≥ 5 Gy. For the PDA cell line investigated, our data show for the first time that single photon doses ≥ 5 Gy effectively inhibit colony formation and induce a G2/M cell cycle arrest. Furthermore, expression levels of immunomodulatory cell surface molecules became altered possibly enhancing the susceptibility of tumour cells to CTL lysis.Despite application of continuously evolving treatment techniques and their individual escalation, prognosis for patients with PDA has remained dismal 1 . The role of radiotherapy in the multimodal treatment approach of PDA has been controversially discussed. In fact, due to its intrinsic properties this tumour entity is generally considered as highly radioresistant and non-immunogenic 2,3 . Recently, several trials have identified hypofractionated photon dose regimens to be associated with increased local control and thus potentially also with survival rates 4-7 . In conventional radiation biology, the use of increased ablative single photon doses commonly overcomes tumour-intrinsic radioresistance by inhibiting repopulation of tumour cells and repair of DNA damage that occur during normofractionated radiotherapy.Several preclinical and clinical trials found increased single photon doses capable of eliciting immunological effects turning irradiated tumours and their stroma into pharmacologically targetable compartments 8 . Regarding PDA, only few preclinical studies have revealed immune stimulatory radiogenic effects so far; the same holds true for studies investigating the clinical benefit of radiotherapy approaches combined with immune checkpoint blockade 9-11 . Currently, there is no consensus about the appropriate photon doses that should be applied in order to induce immunomodulatory alterations in addition to merely anti-proliferative effects. While most of

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Section: Discussioncontrasting

confidence: 99%

Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line

Schröter

Hartmann

Osen

et al. 2020

Sci Rep

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“…Ionizing radiation has been demonstrated in vitro as well as in vivo to stimulate SDF-1/CXCR4 signaling in different human and mouse tumor entities either directly by S-nitrosylation and stabilization of HIF-1α (134) or indirectly via radiation-induced endothelial cell killing and resulting hypoxia (135) or HIF-1α-independent mechanisms (136). Radiation-induced modifications in SDF-1/CXCR4 signaling, in turn, have been reported in gliomas (116, 125, 127, 137), mesotheliomas (138), prostate (139), cervical (140), lung (131, 141) and breast cancer (131). Aside from the direct effect on cancer cells, radiation-induced SDF-1 secretion is also observed in different normal tissues/cells (94, 136, 142–147) or cancer-associated fibroblasts (144).…”

Section: Sdf-1/cxcr4 Function In Tumor Biologymentioning

confidence: 99%

“…Importantly, radiation-modulated SDF-1/CXCR4 signaling has been shown to stimulate tumor re-growth (142, 148), EMT (144), migration (116), invasiveness (81, 127, 138, 141, 144) and metastases (138, 145), as well as homing of hematopoietic progenitor cells and accelerated vasculogenesis (125, 127, 131–133, 136, 137, 142). Thus, radiation-induced SDF-1/CXCR4 signaling may foster radioresistance, malignant progression and recurrence of tumors (94, 125, 139, 149–151).…”

Section: Sdf-1/cxcr4 Function In Tumor Biologymentioning

confidence: 99%

Potential Role of CXCR4 Targeting in the Context of Radiotherapy and Immunotherapy of Cancer

Schilbach²,

et al. 2018

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Cancer immunotherapy has been established as standard of care in different tumor entities. After the first reports on synergistic effects with radiotherapy and the induction of abscopal effects—tumor shrinkage outside the irradiated volume attributed to immunological effects of radiotherapy—several treatment combinations have been evaluated. Different immunotherapy strategies (e.g., immune checkpoint inhibition, vaccination, cytokine based therapies) have been combined with local tumor irradiation in preclinical models. Clinical trials are ongoing in different cancer entities with a broad range of immunotherapeutics and radiation schedules. SDF-1 (CXCL12)/CXCR4 signaling has been described to play a major role in tumor biology, especially in hypoxia adaptation, metastasis and migration. Local tumor irradiation is a known inducer of SDF-1 expression and release. CXCR4 also plays a major role in immunological processes. CXCR4 antagonists have been approved for the use of hematopoietic stem cell mobilization from the bone marrow. In addition, several groups reported an influence of the SDF-1/CXCR4 axis on intratumoral immune cell subsets and anti-tumor immune response. The aim of this review is to merge the knowledge on the role of SDF-1/CXCR4 in tumor biology, radiotherapy and immunotherapy of cancer and in combinatorial approaches.

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“…For the fractionated regimen with 5 × 2 Gy, irradiation was done once daily on days 0-4, whereas for the single fraction regimes, irradiation was performed only on day 0. membrane separated the lower and upper chambers. Methods have been described in detail by our work group before [25]. After 5 hours of incubation at 37 • C, transmigrated iDCs on the lower chamber side were stained with methylene blue and counted with a Leica DC300F microscope.…”

Section: Migrational Analysismentioning

confidence: 99%

Influence of photon, proton and carbon ion irradiation on differentiation, maturation and functionality of dendritic cells

König¹,

Hommertgen²,

Orschiedt³

et al. 2022

Front. Biosci. (Schol Ed)

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While the primary purpose of radiotherapy (RT) is the elimination of cancer cells by inducing DNA-damage, considerable evidence emerges that anti-neoplastic effects extend beyond mere tumor cell killing. These secondary effects are based on activation of dendritic cells (DCs) via induction of antitumoral immune reactions. However, there is an ongoing debate whether or not irradiation of the DCs themselves may negatively affect their maturation and functionality. Human monocytes were irradiated with different absorbed doses (1 × 15 Gy relative biological effectiveness (RBE), 5 × 2 Gy (RBE), 1 × 0.5 Gy (RBE)) with photons, protons and carbon ions. Differentiation and maturation of DCs were assessed by staining of corresponding cell surface molecules and functional analysis of irradiated DCs was based on in vitro analysis of phagocytosis, migration and IL-12 secretion. Irradiation of CD14-positive DCs did not alter surface phenotypes of immature DCs and mature DCs. Not only differentiation, but also functionality of immature DCs regarding phagocytosis, migration and IL-12 secretion capacity was not negatively influenced through RT with photons, protons or carbon ions as well as with different dose levels. After proton irradiation migratory capacity of immature DCs was increased. Our experiments reveal that phenotypic maturation of DCs remains unchanged after RT with different fractionations and after irradiation with particle therapy. Unaffected functionality (phagocytosis, migration and cytokine secretion) after RT of DCs indicated possible persistent potential for inducing adaptive immune response. Additional effects on the immunogenic potential of DCs will be investigated by further functional assays.

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Low-dose photon irradiation induces invasiveness through the SDF-1α/CXCR4 pathway in malignant mesothelioma cells

Cited by 6 publications

References 43 publications

Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line

Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line

Potential Role of CXCR4 Targeting in the Context of Radiotherapy and Immunotherapy of Cancer

Influence of photon, proton and carbon ion irradiation on differentiation, maturation and functionality of dendritic cells

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