Abstract: In 1985 interleukin 6 (IL-6) was first identified as a differentiation factor for B-cells (B-cell stimulatory factor 2) which caused B-cells to mature and produce antibodies. Numerous studies now demonstrate the pleiotropic character of IL-6, which has been shown to possess important functions in the immune system, the regulation of hematopoesis, inflammation and oncogenesis. In the central nervous system (CNS), IL-6 is involved in neurogenesis and the response of neurons and glia-cells to various injuries. CNS infections, cerebral ischaemia, CNS traumata or chronic inflammatory diseases with CNS manifestations such as neuro-lupus or neuro-sarcoidosis are associated with increased IL-6 levels in the cerebrospinal fluid (CSF). Thus, the use of IL-6 as a diagnostic and prognostic tool in these diseases is being investigated. In this review we aim to provide an overview of current studies and evaluate the diagnostic significance of CSF-IL-6.
Introduction Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths worldwide with limited treatment options due to extensive radiation and chemotherapy resistance. Monotherapy with immune checkpoint blockade showed no survival benefit. A combination of immunomodulation and radiotherapy may offer new treatment strategies, as demonstrated for non-small cell lung cancer. Radiation-induced anti-tumour immunity is mediated through cytosolic nucleic acid sensing pathways that drive the expression of interferon beta-1 (IFNB1) and proinflammatory cytokines. Methods Human PDAC cell lines (PANC-1, MIA PaCa-2, BxPC-3) were treated with X-rays and protons. Immunogenic cell death was measured based on HMGB1 release. Cytosolic dsDNA and dsRNA were analysed by immunofluorescence microscopy. Cell cycle progression, MHC-I and PD-L1 expression were determined by flow cytometry. Galectin-1 and IFNB1 were measured by ELISA. The expression levels and the phosphorylation status of the cGAS/STING and RIG-I/MAVS signalling pathways were analysed by western blotting, the expression of IFNB1 and proinflammatory cytokines was determined by RT-qPCR and genome-wide by RNA-seq. CRISPR-Cas9 knock-outs and inhibitors were used to elucidate the relevance of STING, MAVS and NF-κB for radiation-induced IFNB1 activation. Results We demonstrate that a clinically relevant X-ray hypofractionation regimen (3x8 Gy) induces immunogenic cell death and activates IFNB1 and proinflammatory cytokines. Fractionated radiation induces G2/M arrest and accumulation of cytosolic DNA in PDAC cells, which partly originates from mitochondria. RNA-seq analysis shows a global upregulation of type I interferon response and NF-κB signalling in PDAC cells following 3x8 Gy. Radiation-induced immunogenic response is regulated by STING, MAVS and NF-κB. In addition to immunostimulation, radiation also induces immunosuppressive galectin-1. No significant changes in MHC-I or PD-L1 expression were observed. Moreover, PDAC cell lines show similar radiation-induced immune effects when exposed to single-dose protons or photons. Conclusion Our findings provide a rationale for combinatorial radiation-immunomodulatory treatment approaches in PDAC using conventional photon-based or proton beam radiotherapy.
<div>Abstract<p>The ability of focal radiotherapy to promote priming of tumor-specific CD8<sup>+</sup> T cells and increase responses to immunotherapy is dependent on infiltration of the tumor by Batf3-dependent conventional dendritic cell type 1 (cDC1) cells. Such infiltration is driven by radiotherapy-induced IFN type I (IFN-I). Other signals may also modulate cDC1 infiltration of irradiated tumors. Here we found increased expression of adenosine-generating enzymes CD38 and CD73 in irradiated mouse and human breast cancer cells and increased adenosine in mouse tumors following radiotherapy. CD73 blockade alone had no effect. CD73 blockade with radiotherapy restored radiotherapy-induced cDC1 infiltration of tumors in settings where radiotherapy induction of IFN-I was suboptimal. In the absence of radiotherapy-induced IFN-I, blockade of CD73 was required for rejection of the irradiated tumor and for systemic tumor control (abscopal effect) in the context of cytotoxic T-lymphocyte–associated protein 4 blockade. These results suggest that CD73 may be a radiation-induced checkpoint, and that CD73 blockade in combination with radiotherapy and immune checkpoint blockade might improve patient response to therapy.</p></div>
Purpose A relative biological effectiveness (RBE) of 1.1 is commonly used in clinical proton therapy, irrespective of tissue type and depth. This in vitro study was conducted to quantify the RBE of scanned protons as a function of the dose‐averaged linear energy transfer (LET d ) and the sensitivity factor (α/ß) X . Additionally, three phenomenological models (McNamara, Rørvik, and Jones) and one mechanistic model (repair‐misrepair‐fixation, RMF) were applied to the experimentally derived data. Methods Four human cell lines (FaDu, HaCat, Du145, SKMel) with differential (α/ß) X ratios were irradiated in a custom‐designed irradiation setup with doses between 0 and 6 Gy at proximal, central, and distal positions of a 80 mm spread‐out Bragg peak (SOBP) centered at 80 mm (setup A: proton energies 66.5–135.6 MeV) and 155 mm (setup B: proton energies 127.2–185.9 MeV) depth, respectively. LET d values at the respective cell positions were derived from Monte Carlo simulations performed with the treatment planning system (TPS, RayStation). Dosimetric measurements were conducted to verify dose homogeneity and dose delivery accuracy. RBE values were derived for doses that resulted in 90 % (RBE 90 ) and 10 % (RBE 10 ) of cell survival, and survival after a 0.5 Gy dose (RBE 0.5Gy ), 2 Gy dose (RBE 2Gy ), and 6 Gy dose (RBE 6Gy ). Results LET d values at sample positions were 1.9, 2.1, 2.5, 2.8, 4.1, and 4.5 keV/µm. For the cell lines with high (α/ß) X ratios (FaDu, HaCat), the LET d did not impact on the RBE. For low (α/ß) X cell lines (Du145, SKMel), LQ‐derived survival curves indicated a clear correlation of LET d and RBE. RBE 90 values up to 2.9 and RBE 10 values between 1.4 and 1.8 were obtained. Model‐derived RBE predictions slightly overestimated the RBE for the high (α/ß) X cell lines, although all models except the Jones model provided RBE values within the experimental uncertainty. For low (α/ß) X cell lines, no agreement was found between experiments and model predictions, that is, all models underestimated the measured RBE. Conclusions The sensitivity parameter (α/ß) X was observed to be a major influencing factor for the RBE of protons and its sensitivity toward LET d changes. RBE prediction models are applicable for high (α/ß) X cell lines but do not estimate RBE values with sufficient accuracy in low (α/ß) X cell lines.
Zusammenfassung: Interleukin 6 (IL-6) wurde bereits 1985 als Differenzierungsfaktor für B-Zellen (B-cell stimulatory Factor 2) identifiziert, unter dessen Einfluss B-Zellen in Antikörper-bildende Zellen maturierten. In zahlreichen Studien wurde seither der pleiotrope Charakter von IL-6 belegt, das neben seinen Funktionen in der Immunabwehr, auch eine bedeutende Rolle in der Regulation von Hämatopoese, Inflammation und Onkogenese übernimmt. In Bezug auf das ZNS wurde die Beteiligung von IL-6 an der Neurogenese sowie an der Reaktion von Neuronen und Glia-Zellen auf Verletzungen beschrieben. Infektionen des ZNS, cerebrale Ischämien, schwere ZNS-Traumata oder chronisch entzündliche Erkrankungen wie Neuro-Lupus oder Neuro-Sarkoidose gehen mit erhöhten IL-6 Konzentrationen im Liquor einher. Aufgrund der Präsenz des Neuropoetins IL-6 im Rahmen dieser Erkrankungen wird ein möglicher Einsatz des Parameters IL-6 im Liquor zur Diagnostik und, in manchen Fällen, zur Verlaufsbeurteilung und Therapieüberwachung überprüft. In diesem Review geben wir einen Überblick über die derzeitige Studienlage und die diagnostische Wertigkeit von IL-6 im Liquor.
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