Microparticles from tumors exposed to radiation promote immune evasion in part by PD-L1.

Radiotherapy induces immune-related responses in cancer patients by various mechanisms. Here, we investigate the immunomodulatory role of tumor-derived microparticles (TMPs)-extracellular vesicles shed from tumor cells-following radiotherapy. We demonstrate that breast carcinoma cells exposed to radiation shed TMPs containing elevated levels of immune-modulating proteins, one of which is programmed death-ligand 1 (PD-L1). These TMPs inhibit cytotoxic T lymphocyte (CTL) activity both in vitro and in vivo, and thus promote tumor growth. Evidently, adoptive transfer of CTLs pre-cultured with TMPs from irradiated breast carcinoma cells increases tumor growth rates in mice recipients in comparison with control mice receiving CTLs pre-cultured with TMPs from untreated tumor cells. In addition, blocking the PD-1-PD-L1 axis, either genetically or pharmacologically, partially alleviates TMP-mediated inhibition of CTL activity, suggesting that the immunomodulatory effects of TMPs in response to radiotherapy is mediated, in part, by PD-L1. Overall, our findings provide mechanistic insights into the tumor immune surveillance state in response to radiotherapy and suggest a therapeutic synergy between radiotherapy and immune checkpoint inhibitors.

Radiation induces proinflammatory dysbiosis: transmission of inflammatory susceptibility by host cytokine induction.

OBJECTIVE: Radiation proctitis (RP) is a complication of pelvic radiotherapy which affects both the host and microbiota. Herein we assessed the radiation effect on microbiota and its relationship to tissue damage using a rectal radiation mouse model. DESIGN: We evaluated luminal and mucosa-associated dysbiosis in irradiated and control mice at two postradiation time points and correlated it with clinical and immunological parameters. Epithelial cytokine response was evaluated using bacterial-epithelial co-cultures. Subsequently, germ-free (GF) mice were colonised with postradiation microbiota and controls and exposed to radiation, or dextran sulfate-sodium (DSS). Interleukin (IL)-1ß correlated with tissue damage and was induced by dysbiosis. Therefore, we tested its direct role in radiation-induced damage by IL-1 receptor antagonist administration to irradiated mice. RESULTS: A postradiation shift in microbiota was observed. A unique microbial signature correlated with histopathology. Increased colonic tumor necrosis factor (TNF)α, IL-1ß and IL-6 expression was observed at two different time points. Adherent microbiota from RP differed from those in uninvolved segments and was associated with tissue damage. Using bacterial-epithelial co-cultures, postradiation microbiota enhanced IL-1ß and TNFα expression compared with naïve microbiota. GF mice colonisation by irradiated microbiota versus controls predisposed mice to both radiation injury and DSS-induced colitis. IL-1 receptor antagonist administration ameliorated intestinal radiation injury. CONCLUSIONS: The results demonstrate that rectal radiation induces dysbiosis, which transmits radiation and inflammatory susceptibility and provide evidence that microbial-induced radiation tissue damage is at least in part mediated by IL-1ß. Environmental factors may affect the host via modifications of the microbiome and potentially allow for novel interventional approaches via its manipulation.

Room scatter effects in Total Skin Electron Irradiation: Monte Carlo simulation study.

PURPOSE: Total Skin Electron Irradiation (TSEI) is a complex technique which usually involves the use of large electron fields and the dual-field approach. In this situation, many electrons scattered from the treatment room floor are produced. However, no investigations of the effect of scattered electrons in TSEI treatments have been reported. The purpose of this work was to study the contribution of floor scattered electrons to skin dose during TSEI treatment using Monte Carlo (MC) simulations. METHODS: All MC simulations were performed with the EGSnrc code. Influence of beam energy, dual-field angle, and floor material on the contribution of floor scatter was investigated. Spectrum of the scattered electrons was calculated. Measurements of dose profile were performed in order to verify MC calculations. RESULTS: Floor scatter dependency on the floor material was observed (at 20 cm from the floor, scatter contribution was about 21%, 18%, 15%, and 12% for iron, concrete, PVC, and water, respectively). Although total dose profiles exhibited slight variation as functions of beam energy and dual-field angle, no dependence of the floor scatter contribution on the beam energy or dual-field angle was found. The spectrum of the scattered electrons was almost uniform between a few hundred KeV to 4 MeV, and then decreased linearly to 6 MeV. CONCLUSIONS: For the TSEI technique, dose contribution due to the electrons scattered from the room floor may be clinically significant and should be taken into account during design and commissioning phases. MC calculations can be used for this task.

Perturbation effects of the carbon fiber-PEEK screws on radiotherapy dose distribution.

Radiation therapy, in conjunction with surgical implant fixation, is a common combined treatment in cases of bone metastases. However, metal implants generally used in orthopedic implants perturb radiation dose distributions. Carbon-Fiber Reinforced Polyetheretherketone (CFR-PEEK) material has been recently introduced for production of intramedullary nails and plates. The purpose of this work was to investigate the perturbation effects of the new CFR-PEEK screws on radiotherapy dose distributions and to evaluate these effects in comparison with traditional titanium screws. The investigation was performed by means of Monte Carlo (MC) simulations for a 6 MV photon beam. The project consisted of two main stages. First, a comparison of measured and MC calculated doses was performed to verify the validity of the MC simulation results for different materials. For this purpose, stainless steel, titanium, and CFR-PEEK plates of various thicknesses were used for attenuation and backscatter measurements in a solid water phantom. For the same setup, MC dose calculations were performed. Next, MC dose calculations for titanium, CFR-PEEK screws, and CFR-PEEK screws with ultrathin titanium coating were performed. For the plates, the results of our MC calculations for all materials were found to be in good agreement with the measurements. This indicates that the MC model can be used for calculation of dose perturbation effects caused by the screws. For the CFR-PEEK screws, the maximum dose perturbation was less than 5%, compared to more than 30% perturbation for the titanium screws. Ultrathin titanium coating had a negligible effect on the dose distribution. CFR-PEEK implants have good prospects for use in radiotherapy because of minimal dose alteration and the potential for more accurate treatment planning. This could favorably influence treatment efficiency and decrease possible over- and underdose of adjacent tissues. The use of such implants has potential clinical advantages in the treatment of bone metastases.

Validation of total skin electron irradiation (TSEI) technique dosimetry data by Monte Carlo simulation.

Total skin electron irradiation (TSEI) is a complex technique which requires many nonstandard measurements and dosimetric procedures. The purpose of this work was to validate measured dosimetry data by Monte Carlo (MC) simulations using EGSnrc-based codes (BEAMnrc and DOSXYZnrc). Our MC simulations consisted of two major steps. In the first step, the incident electron beam parameters (energy spectrum, FWHM, mean angular spread) were adjusted to match the measured data (PDD and profile) at SSD = 100 cm for an open field. In the second step, these parameters were used to calculate dose distributions at the treatment distance of 400 cm. MC simulations of dose distributions from single and dual fields at the treatment distance were performed in a water phantom. Dose distribution from the full treatment with six dual fields was simulated in a CT-based anthropomorphic phantom. MC calculations were compared to the available set of measurements used in clinical practice. For one direct field, MC calculated PDDs agreed within 3%/1 mm with the measurements, and lateral profiles agreed within 3% with the measured data. For the OF, the measured and calculated results were within 2% agreement. The optimal angle of 17° was confirmed for the dual field setup. Dose distribution from the full treatment with six dual fields was simulated in a CT-based anthropomorphic phantom. The MC-calculated multiplication factor (B12-factor), which relates the skin dose for the whole treatment to the dose from one calibration field, for setups with and without degrader was 2.9 and 2.8, respectively. The measured B12-factor was 2.8 for both setups. The difference between calculated and measured values was within 3.5%. It was found that a degrader provides more homogeneous dose distribution. The measured X-ray contamination for the full treatment was 0.4%; this is compared to the 0.5% X-ray contamination obtained with the MC calculation. Feasibility of MC simulation in an anthropomorphic phantom for a full TSEI treatment was proved and is reported for the first time in the literature. The results of our MC calculations were found to be in general agreement with the measurements, providing a promising tool for further studies of dose distribution calculations in TSEI.

Dequalinium blocks macrophage-induced metastasis following local radiation.

A major therapeutic obstacle in clinical oncology is intrinsic or acquired resistance to therapy, leading to subsequent relapse. We have previously shown that systemic administration of different cytotoxic drugs can induce a host response that contributes to tumor angiogenesis, regrowth and metastasis. Here we characterize the host response to a single dose of local radiation, and its contribution to tumor progression and metastasis. We show that plasma from locally irradiated mice increases the migratory and invasive properties of colon carcinoma cells. Furthermore, locally irradiated mice intravenously injected with CT26 colon carcinoma cells succumb to pulmonary metastasis earlier than their respective controls. Consequently, orthotopically implanted SW480 human colon carcinoma cells in mice that underwent radiation, exhibited increased metastasis to the lungs and liver compared to their control tumors. The irradiated tumors exhibited an increase in the colonization of macrophages compared to their respective controls; and macrophage depletion in irradiated tumor-bearing mice reduces the number of metastatic lesions. Finally, the anti-tumor agent, dequalinium-14, in addition to its anti-tumor effect, reduces macrophage motility, inhibits macrophage infiltration of irradiated tumors and reduces the extent of metastasis in locally irradiated mice. Overall, this study demonstrates the adverse effects of local radiation on the host that result in macrophage-induced metastasis.