Publications by authors named "Udo S Gaipl"

127 Publications

Radiotherapy and the immune system: More than just immune suppression.

Stem Cells 2021 May 7. Epub 2021 May 7.

Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Radiotherapy (RT) is still one of the standard cancer therapies with up to two third of all cancer patients with solid tumors being irradiated in the course of their disease. The aim of using ionizing radiation in fractionated treatment schedules was always to achieve local tumor control by inducing DNA damage which can be repaired by surrounding normal tissue but leads to cell death in tumor cells. Meanwhile, it is known that RT also has immunological effects reshaping the tumor microenvironment. Nevertheless, RT alone often fails to elicit potent antitumor immune responses as these effects can be immunostimulatory as well as immunosuppressive. Here, we discuss how immunotherapies can be exploited in combined therapies to boost RT-induced antitumor immune responses or to counteract preexisting and RT-mediated immunosuppression to improve local and systemic tumor control. Furthermore, we highlight some parameters of radioimmunotherapies (RITs) which are under investigation for potential optimizations and how RIT approaches are tested in first phases II and III trials. Finally, we discuss how RT might affect normal and cancer stem cells.
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http://dx.doi.org/10.1002/stem.3391DOI Listing
May 2021

Identification of 15 lncRNAs Signature for Predicting Survival Benefit of Advanced Melanoma Patients Treated with Anti-PD-1 Monotherapy.

Cells 2021 Apr 22;10(5). Epub 2021 Apr 22.

Department of Radiation Oncology, Universitätsklinikum Erlangen, 91054 Erlangen, Germany.

The blockade of programmed cell death protein 1 (PD-1) as monotherapy has been widely used in melanoma, but to identify melanoma patients with survival benefit from anti-PD-1 monotherapy is still a big challenge. There is an urgent need for prognostic signatures improving the prediction of immunotherapy responses of these patients. We analyzed transcriptomic data of pre-treatment tumor biopsies and clinical profiles in advanced melanoma patients receiving only anti-PD-1 monotherapy (nivolumab or pembrolizumab) from the PRJNA356761 and PRJEB23709 data sets as the training and validation cohort, respectively. Weighted gene co-expression network analysis was used to identify the key module, then least absolute shrinkage and selection operator was conducted to determine prognostic-related long noncoding RNAs (lncRNAs). Subsequently, the differentially expressed genes between different clusters were identified, and their function and pathway annotation were performed. In this investigation, 92 melanoma patients with complete survival information (51 from training cohort and 41 from validation cohort) were included in our analyses. We initiallyidentified the key module (skyblue) by weighted gene co-expression network analysis, and then identified a 15 predictive lncRNAs (AC010904.2, LINC01126, AC012360.1, AC024933.1, AL442128.2, AC022211.4, AC022211.2, AC127496.5, NARF-AS1, AP000919.3, AP005329.2, AC023983.1, AC023983.2, AC139100.1, and AC012615.4) signature in melanoma patients treated with anti-PD-1 monotherapy by least absolute shrinkage and selection operator in the training cohort. These results were then validated in the validation cohort. Finally, enrichment analysis showed that the functions of differentially expressed genes between two consensus clusters were mainly related to the immune process and treatment. In summary, the 15 lncRNAs signature is a novel effective predictor for prognosis in advanced melanoma patients treated with anti-PD-1 monotherapy.
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http://dx.doi.org/10.3390/cells10050977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143567PMC
April 2021

Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors.

BMC Cancer 2021 Mar 24;21(1):314. Epub 2021 Mar 24.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstraße 27, 91054, Erlangen, Germany.

Background: Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far.

Methods: The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE.

Results: Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were "weight change", "difficulty to grip things", "bloody or mucous stool" and "insomnia". Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire.

Conclusion: Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on "weight change" and "insomnia" may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients.

Trial Registration: ClinicalTrials.gov, NCT03453892 . Registered on 05 March 2018.
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http://dx.doi.org/10.1186/s12885-021-08006-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992796PMC
March 2021

Combinations of Radiotherapy with Vaccination and Immune Checkpoint Inhibition Differently Affect Primary and Abscopal Tumor Growth and the Tumor Microenvironment.

Cancers (Basel) 2021 Feb 9;13(4). Epub 2021 Feb 9.

Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, 91054 Erlangen, Germany.

Radiotherapy (RT) is known to have immune-modulatory properties. We hypothesized that RT and inactivated whole tumor cell vaccines generated with high hydrostatic pressure (HHP) synergize to retard the tumor growth which can be additionally improved with anti-PD-1 treatment. In abscopal tumor models, we injected mice with B16-F10 melanoma or TS/A mammary tumors. To evaluate the efficiency of RT in combination with HHP vaccines, we locally irradiated only one tumor with 2 × 8 Gy or 3 × 8 Gy. HHP vaccines further retarded the growth of locally irradiated (2 × 8 Gy) tumors. However, HHP vaccination combined with RT failed to induce abscopal anti-tumor immune responses, namely those to non-irradiated tumors, and even partly abrogated those which were induced with RT plus anti-PD-1. In the latter group, the abscopal effects were accompanied by an elevated infiltration of CD8+ T cells, monocytes/macrophages, and dendritic cells. 3 × 8 Gy failed to induce abscopal effects in association with increased expression of immunosuppressive checkpoint molecules compared to 2 × 8 Gy. We conclude that HHP vaccines induce anti-tumor effects, but only if the tumor microenvironment was previously modulated by hypofractionated RT with not too many fractions, but failed to improve RT plus anti-PD-induced abscopal responses that are characterized by distinct immune alterations.
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http://dx.doi.org/10.3390/cancers13040714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916259PMC
February 2021

Gas plasma irradiation of breast cancers promotes immunogenicity, tumor reduction, and an abscopal effect in vivo.

Oncoimmunology 2020 12 29;10(1):1859731. Epub 2020 Dec 29.

Center for Innovation Competence (ZIK) Plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Greifswald, Germany.

While many new and emerging therapeutic concepts have appeared throughout the last decades, cancer still is fatal in many patients. At the same time, the importance of immunology in oncotherapy is increasingly recognized, not only since the advent of checkpoint therapy. Among the many types of tumors, also breast cancer has an immunological dimension that might be exploited best by increasing the immunogenicity of the tumors in the microenvironment. To this end, we tested a novel therapeutic concept, gas plasma irradiation, for its ability to promote the immunogenicity and increase the toxicity of breast cancer cells in vitro and in vivo. Mechanistically, this emerging medical technology is employing a plethora of reactive oxygen species being deposited on the target cells and tissues. Using 2D cultures and 3D tumor spheroids, we found gas plasma-irradiation to drive apoptosis and immunogenic cancer cell death (ICD) in vitro, as evidenced by an increased expression of calreticulin, heat-shock proteins 70 and 90, and MHC-I. In 4T1 breast cancer-bearing mice, the gas plasma irradiation markedly decreased tumor burden and increased survival. Interestingly, non-treated tumors injected in the opposite flank of mice exposed to our novel treatment also exhibited reduced growth, arguing for an abscopal effect. This was concomitant with an increase of apoptosis and tumor-infiltrating CD4 and CD8 T-cells as well as dendritic cells in the tissues. In summary, we found gas plasma-irradiated murine breast cancers to induce toxicity and augmented immunogenicity, leading to reduced tumor growth at a site remote to the treatment area.
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http://dx.doi.org/10.1080/2162402X.2020.1859731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781742PMC
December 2020

Radon Exposure-Therapeutic Effect and Cancer Risk.

Int J Mol Sci 2020 Dec 30;22(1). Epub 2020 Dec 30.

Translational Radiation Biology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.

Largely unnoticed, all life on earth is constantly exposed to low levels of ionizing radiation. Radon, an imperceptible natural occurring radioactive noble gas, contributes as the largest single fraction to radiation exposure from natural sources. For that reason, radon represents a major issue for radiation protection. Nevertheless, radon is also applied for the therapy of inflammatory and degenerative diseases in galleries and spas to many thousand patients a year. In either case, chronic environmental exposure or therapy, the effect of radon on the organism exposed is still under investigation at all levels of interaction. This includes the physical stage of diffusion and energy deposition by radioactive decay of radon and its progeny and the biological stage of initiating and propagating a physiologic response or inducing cancer after chronic exposure. The purpose of this manuscript is to comprehensively review the current knowledge of radon and its progeny on physical background, associated cancer risk and potential therapeutic effects.
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http://dx.doi.org/10.3390/ijms22010316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796069PMC
December 2020

Prospective Evaluation of All-lesion Versus Single-lesion Radiotherapy in Combination With PD-1/PD-L1 Immune Checkpoint Inhibitors.

Front Oncol 2020 29;10:576643. Epub 2020 Oct 29.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Background: Local ablative treatments improve survival in patients with oligometastatic disease in addition to chemotherapy. The application of immune checkpoint inhibitors prolonged patients' survival in different tumor entities. This raises the question if patients still benefit from intensified local treatments in combination with a more efficient systemic treatment with immune checkpoint inhibitors.

Methods: The prospective non-interventional ST-ICI trial investigates treatment with PD-1/PD-L1 (Programmed cell death protein 1/Programmed cell death 1 ligand 1) immune checkpoint inhibitors and radiotherapy in different tumor entities. Patients who started radiotherapy and immunotherapy concomitantly were included in this interim analysis. In this cohort patients with all-lesion radiotherapy (all tumor lesions irradiated, al-RT) were compared to patients with radiotherapy to only a single of their tumor lesions (single-lesion radiotherapy, sl-RT). Endpoints of the interim analysis were progression-free survival (PFS), overall survival (OS) and time to progression (TTP).

Results: A total of 104 patients were registered between April 2017 and August 2019. Fifty patients started immune checkpoint inhibitor treatment and radiotherapy concomitantly and were included. Most frequent tumor entities were non-small cell lung cancer (62%) followed by head and neck squamous cell cancer (26%). Most frequent location of radiotherapy was lung (34%) and central nervous system (20%). Median duration of follow-up was 8.6 months beginning with first administration of the immune-checkpoint-inhibitor. Median PFS was 9.2 months (95% CI, 5.8 - 12.6) in the al-RT group and 3.0 months (95% CI, 2.5 - 3.5) in the sl-RT group (p<0.001). Median OS was 11.6 months (95% CI, 8.1 - 15.1) in the al-RT group and 4.2 months (95% CI, 3.0 - 5.4) in the sl-RT group (p=0.007). Median TTP was not reached in the al-RT group compared to 4.6 months (95% CI, 1.1-8.0) in the sl-RT group (p=0.028). Univariate Cox regression analyses computed tumor entity, histology, central nervous system metastases, immunotherapy drug and al-RT as predictors of OS (with an effect p-value of ≤ 0.1). In the multivariable analysis only tumor entity and al-RT remained prognostic factors for OS.

Conclusion: Patients with PD-1/PD-L1 immune checkpoint inhibitor therapy benefit from local radiotherapy to all known lesions compared to single-lesion radiotherapy regarding PFS and OS.
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http://dx.doi.org/10.3389/fonc.2020.576643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673414PMC
October 2020

Defining Metaniches in the Oral Cavity According to Their Microbial Composition and Cytokine Profile.

Int J Mol Sci 2020 Nov 3;21(21). Epub 2020 Nov 3.

Department of Orthodontics and Orofacial Orthopedics, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Glückstr. 11, 91054 Erlangen, Germany.

The human oral microbiota consists of over 700 widespread taxa colonizing the oral cavity in several anatomically diverse oral niches. Lately, sequencing of the 16S rRNA genes has become an acknowledged, culture-independent method to characterize the oral microbiota. However, only a small amount of data are available concerning microbial differences between oral niches in periodontal health and disease. In the context of periodontitis, the cytokine expression in the gingival crevicular fluid has been studied in detail, whereas little is known about the cytokine profile in hard and soft tissue biofilms. In order to characterize oral niches in periodontal health, the oral microbiota and cytokine pattern were analyzed at seven different sites (plaque (P), gingival crevicular fluid (GCF), saliva (S), tongue (T), hard palate (HP), cheek (C) and sublingual area (U)) of 20 young adults using next-generation sequencing and multiplex immunoassays. Site-specific microbial compositions were detected, which clustered into three distinct metaniches ("P-GCF", "S-T-HP" and "C-U") and were associated with niche-/metaniche-specific cytokine profiles. Our findings allow the definition of distinct metaniches according to their microbial composition, partly reflected by their cytokine profile, and provide new insights into microenvironmental similarities between anatomical diverse oral niches.
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http://dx.doi.org/10.3390/ijms21218218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663680PMC
November 2020

Prospective evaluation of the prognostic value of immune-related adverse events in patients with non-melanoma solid tumour treated with PD-1/PD-L1 inhibitors alone and in combination with radiotherapy.

Eur J Cancer 2020 11 9;140:55-62. Epub 2020 Oct 9.

Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.

Background: Prospective data about the prognostic value of immune-related adverse events (irAEs) in non-melanoma solid tumours are rare. The prognostic value of irAEs in patients treated with combined radiotherapy and immunotherapy is currently unknown.

Patients And Methods: The prospective non-interventional ST-ICI trial investigates treatment response of tumour patients to anti-programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors alone and in combination with radiotherapy and possible predictive markers. Patients undergoing immunotherapy or immunoradiotherapy were surveyed for irAEs.

Results: A total of 104 patients were included of whom 29 patients (28%) developed irAEs. Additional radiotherapy was performed in 50 patients (48%). Main tumour entities within the entire cohort were non-small cell lung cancer (NSCLC) (44%) and head and neck squamous cell carcinoma (42%). The rate of irAEs did not differ in patients with and without radiotherapy (p = 0.668). Patients who developed irAEs had longer overall survival (OS) (median: 22.8 months versus 9.0 months without irAEs, p = 0.001) and progression-free survival (PFS) (median: 7.8 months versus 3.2 months without irAEs, p = 0.002). In the subgroup with combined radiotherapy, patients with irAEs also had longer OS (median: 22.8 months versus 7.1 months without irAEs, p = 0.005) and PFS (median: 8.8 months versus 3.0 months without irAEs, p = 0.005). On multivariate analysis only PD-L1 on tumour cells (p = 0.049) and irAEs (p = 0.001) remained independent predictors of OS.

Conclusion: The development of irAEs represents a favourable prognostic parameter in patients undergoing immunotherapy and immunoradiotherapy for solid tumours.
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http://dx.doi.org/10.1016/j.ejca.2020.09.001DOI Listing
November 2020

Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8.

J Immunother Cancer 2020 10;8(2)

Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany.

Background: To determine safety and efficacy of single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab in stage III-IVB head and neck cancer.

Methods: Patients received a single cycle of cisplatin 30 mg/m² on days 1-3 and docetaxel 75 mg/m² on day 1 combined with durvalumab 1500 mg fix dose on day 5 and tremelimumab 75 mg fix dose on day 5. Patients with pathologic complete response (pCR) in the rebiopsy after induction treatment or at least 20% increase of intratumoral CD8+ cell density in the rebiopsy compared with baseline entered radioimmunotherapy with concomitant durvalumab/tremelimumab. The objective of this interim analysis was to analyze safety and efficacy of the chemoimmunotherapy-induction treatment before radioimmunotherapy.

Results: A total of 57 patients were enrolled, 56 were treated. Median pretreatment intratumoral CD8+ cell density was 342 cells/mm². After induction treatment, 27 patients (48%) had a pCR in the rebiopsy and further 25 patients (45%) had a relevant increase of intratumoral CD8+ cells (median increase by a factor of 3.0). Adverse event (AE) grade 3-4 appeared in 38 patients (68%) and mainly consisted of leukopenia (43%) and infections (29%). Six patients (11%) developed grade 3-4 immune-related AE. Univariate analysis computed p16 positivity, programmed death ligand 1 immune cell area and intratumoral CD8+ cell density as predictors of pCR. On multivariable analysis, intratumoral CD8+ cell density predicted pCR independently (OR 1.0012 per cell/mm², 95% CI 1.0001 to 1.0022, p=0.016). In peripheral blood CD8+ cells, the coexpression of programmed death protein 1 significantly increased especially in patients with pCR.

Conclusions: Single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab is feasible and achieves a high biopsy-proven pCR rate.
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http://dx.doi.org/10.1136/jitc-2020-001378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539609PMC
October 2020

Priming of Anti-tumor Immune Mechanisms by Radiotherapy Is Augmented by Inhibition of Heat Shock Protein 90.

Front Oncol 2020 27;10:1668. Epub 2020 Aug 27.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.

Radiotherapy is an essential part of multi-modal cancer therapy. Nevertheless, for certain cancer entities such as colorectal cancer (CRC) the indications of radiotherapy are limited due to anatomical peculiarities and high radiosensitivity of the surrounding normal tissue. The development of molecularly targeted, combined modality approaches may help to overcome these limitations. Preferably, such strategies should not only enhance radiation-induced tumor cell killing and the abrogation of tumor cell clonogenicity, but should also support the stimulation of anti-tumor immune mechanisms - a phenomenon which moved into the center of interest of preclinical and clinical research in radiation oncology within the last decade. The present study focuses on inhibition of heat shock protein 90 (HSP90) whose combination with radiotherapy has previously been reported to exhibit convincing therapeutic synergism in different preclinical cancer models. By employing and analyses, we examined if this therapeutic synergism also applies to the priming of anti-tumor immune mechanisms in model systems of CRC. Our results indicate that the combination of HSP90 inhibitor treatment and ionizing irradiation induced apoptosis in colorectal cancer cells with accelerated transit into secondary necrosis in a hyperactive Kras-dependent manner. During secondary necrosis, dying cancer cells released different classes of damage-associated molecular patterns (DAMPs) that stimulated migration and recruitment of monocytic cells and . Additionally, these dying cancer cell-derived DAMPs enforced the differentiation of a monocyte-derived antigen presenting cell (APC) phenotype which potently triggered the priming of allogeneic T cell responses . In summary, HSP90 inhibition - apart from its radiosensitizing potential - obviously enables and supports the initial steps of anti-tumor immune priming upon radiotherapy and thus represents a promising partner for combined modality approaches. The therapeutic performance of such strategies requires further in-depth analyses, especially for but not only limited to CRC.
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http://dx.doi.org/10.3389/fonc.2020.01668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481363PMC
August 2020

The Influence of Radiation on Bone and Bone Cells-Differential Effects on Osteoclasts and Osteoblasts.

Int J Mol Sci 2020 Sep 2;21(17). Epub 2020 Sep 2.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

The bone is a complex organ that is dependent on a tight regulation between bone formation by osteoblasts (OBs) and bone resorption by osteoclasts (OCs). These processes can be influenced by environmental factors such as ionizing radiation (IR). In cancer therapy, IR is applied in high doses, leading to detrimental effects on bone, whereas radiation therapy with low doses of IR is applied for chronic degenerative and inflammatory diseases, with a positive impact especially on bone homeostasis. Moreover, the effects of IR are of particular interest in space travel, as astronauts suffer from bone loss due to space radiation and microgravity. This review summarizes the current state of knowledge on the effects of IR on bone with a special focus on the influence on OCs and OBs, as these cells are essential in bone remodeling. In addition, the influence of IR on the bone microenvironment is discussed. In summary, the effects of IR on bone and bone remodeling cells strongly depend on the applied radiation dose, as differential results are provided from in vivo as well as in vitro studies with varying doses of IR. Furthermore, the isolated effects of IR on a single cell type are difficult to determine, as the bone cells and bone microenvironment are building a tightly regulated network, influencing on one another. Therefore, future research is necessary in order to elucidate the influence of different bone cells on the overall radiation-induced effects on bone.
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http://dx.doi.org/10.3390/ijms21176377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504528PMC
September 2020

Development and Validation of a Gene Signature for Prediction of Relapse in Stage I Testicular Germ Cell Tumors.

Front Oncol 2020 30;10:1147. Epub 2020 Jul 30.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany.

Testicular germ cell tumors (TGCTs) are commonly diagnosed tumors in young men. However, a satisfactory approach to predict relapse of stage I TGCTs is still lacking. Therefore, this study aimed to develop a robust risk score model for stage I TGCTs. RNA-sequence data of stage I TGCTs and normal testis samples were downloaded and analyzed to identify different expression genes. Gene-based prognostic model was constructed in The Cancer Genome Atlas (TCGA) using least absolute shrinkage and selection operator (LASSO) regression analysis and validated in GSE99420 dataset. Potential biological functions of the genes in prognostic model were determined via Gene Set Enrichment Analysis (GSEA) between high-risk and low-risk patients. A total of 9,391 differentially expressed genes and 84 prognosis-related genes were identified. An eight-gene-based risk score model was constructed to divide patients into high or low risk of relapse. The low-risk patients had a significantly better relapse-free survival (RFS) than high-risk patients in both training and validation cohorts (HR = 0.129, 95% CI = 0.059-0.284, < 0.001; HR = 0.277, 95% CI = 0.116-0.661, = 0.004, respectively). The area under the receiver operating characteristic curve (AUC) values at 5 years was 0.805 and 0.724 in the training and validation cohorts, respectively. Functional enrichment analyses showed that DNA replication, ribosome, cell cycle, and TGF-beta signaling pathway may contribute to the relapse process. In summary, our analysis provided a novel eight-gene signature that could predict RFS in stage I TGCT patients.
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http://dx.doi.org/10.3389/fonc.2020.01147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412879PMC
July 2020

Low Dose Radiation Therapy, Particularly with 0.5 Gy, Improves Pain in Degenerative Joint Disease of the Fingers: Results of a Retrospective Analysis.

Int J Mol Sci 2020 Aug 14;21(16). Epub 2020 Aug 14.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

Low-dose radiation therapy (LDRT) has been successfully established for decades as an alternative analgesic treatment option for patients suffering from chronic degenerative and inflammatory diseases. In this study, 483 patients were undergoing LDRT for degenerative joint disease of the fingers and thumb at the University Hospital Erlangen between 2004 and 2019. Radiotherapy was applied according to the German guidelines for LDRT. Several impact factors on therapeutic success, such as the age and gender, the number of affected fingers, the single and cumulative dose, as well as the number of series, were investigated. In summary, 70% of the patients showed an improvement of their pain following LDRT. No significant impact was found for the factors age, gender, the number of series or the cumulative dosage. Patients with an involvement of the thumb showed a significantly worse outcome compared to patients with an isolated affection of the fingers. In this cohort, patients receiving a single dose of 0.5 Gy reported a significantly better outcome than patients receiving 1.0 Gy, strongly suggesting a reduction in the total dose. In summary, LDRT is a good alternative treatment option for patients suffering from degenerative and inflammatory joint disease of the fingers.
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http://dx.doi.org/10.3390/ijms21165854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461565PMC
August 2020

Integrating Loco-Regional Hyperthermia Into the Current Oncology Practice: SWOT and TOWS Analyses.

Front Oncol 2020 12;10:819. Epub 2020 Jun 12.

Centre for Radiation Oncology KSA-KSB, Kantonsspital Aarau, Aarau, Switzerland.

Moderate hyperthermia at temperatures between 40 and 44°C is a multifaceted therapeutic modality. It is a potent radiosensitizer, interacts favorably with a host of chemotherapeutic agents, and, in combination with radiotherapy, enforces immunomodulation akin to " tumor vaccination." By sensitizing hypoxic tumor cells and inhibiting repair of radiotherapy-induced DNA damage, the properties of hyperthermia delivered together with photons might provide a tumor-selective therapeutic advantage analogous to high linear energy transfer (LET) neutrons, but with less normal tissue toxicity. Furthermore, the high LET attributes of hyperthermia thermoradiobiologically are likely to enhance low LET protons; thus, proton thermoradiotherapy would mimic C ion therapy. Hyperthermia with radiotherapy and/or chemotherapy substantially improves therapeutic outcomes without enhancing normal tissue morbidities, yielding level I evidence reported in several randomized clinical trials, systematic reviews, and meta-analyses for various tumor sites. Technological advancements in hyperthermia delivery, advancements in hyperthermia treatment planning, online invasive and non-invasive MR-guided thermometry, and adherence to quality assurance guidelines have ensured safe and effective delivery of hyperthermia to the target region. Novel biological modeling permits integration of hyperthermia and radiotherapy treatment plans. Further, hyperthermia along with immune checkpoint inhibitors and DNA damage repair inhibitors could further augment the therapeutic efficacy resulting in synthetic lethality. Additionally, hyperthermia induced by magnetic nanoparticles coupled to selective payloads, namely, tumor-specific radiotheranostics (for both tumor imaging and radionuclide therapy), chemotherapeutic drugs, immunotherapeutic agents, and gene silencing, could provide a comprehensive tumor-specific theranostic modality akin to "magic (nano)bullets." To get a realistic overview of the strength (S), weakness (W), opportunities (O), and threats (T) of hyperthermia, a SWOT analysis has been undertaken. Additionally, a TOWS analysis categorizes future strategies to facilitate further integration of hyperthermia with the current treatment modalities. These could gainfully accomplish a safe, versatile, and cost-effective enhancement of the existing therapeutic armamentarium to improve outcomes in clinical oncology.
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http://dx.doi.org/10.3389/fonc.2020.00819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303270PMC
June 2020

Low-dose radiation therapy for COVID-19 pneumopathy: what is the evidence?

Strahlenther Onkol 2020 08 9;196(8):679-682. Epub 2020 May 9.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany.

In the current dismal situation of the COVID-19 pandemic, effective management of patients with pneumonia and acute respiratory distress syndrome is of vital importance. Due to the current lack of effective pharmacological concepts, this situation has caused interest in (re)considering historical reports on the treatment of patients with low-dose radiation therapy for pneumonia. Although these historical reports are of low-level evidence per se, hampering recommendations for decision-making in the clinical setting, they indicate effectiveness in the dose range between 0.3 and 1 Gy, similar to more recent dose concepts in the treatment of acute and chronic inflammatory/degenerative benign diseases with, e.g., a single dose per fraction of 0.5 Gy. This concise review aims to critically review the evidence for low-dose radiation treatment of COVID-19 pneumopathy and discuss whether it is worth investigating in the present clinical situation.
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http://dx.doi.org/10.1007/s00066-020-01635-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211051PMC
August 2020

Differences of the Immune Phenotype of Breast Cancer Cells after Ex Vivo Hyperthermia by Warm-Water or Microwave Radiation in a Closed-Loop System Alone or in Combination with Radiotherapy.

Cancers (Basel) 2020 Apr 27;12(5). Epub 2020 Apr 27.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

The treatment of breast cancer by radiotherapy can be complemented by hyperthermia. Little is known about how the immune phenotype of tumor cells is changed thereby, also in terms of a dependence on the heating method. We developed a sterile closed-loop system, using either a warm-water bath or a microwave at 2.45 GHz to examine the impact of ex vivo hyperthermia on cell death, the release of HSP70, and the expression of immune checkpoint molecules (ICMs) on MCF-7 and MDA-MB-231 breast cancer cells by multicolor flow cytometry and ELISA. Heating was performed between 39 and 44 °C. Numerical process simulations identified temperature distributions. Additionally, irradiation with 2 × 5 Gy or 5 × 2 Gy was applied. We observed a release of HSP70 after hyperthermia at all examined temperatures and independently of the heating method, but microwave heating was more effective in cell killing, and microwave heating with and without radiotherapy increased subsequent HSP70 concentrations. Adding hyperthermia to radiotherapy, dynamically or individually, affected the expression of the ICM PD-L1, PD-L2, HVEM, ICOS-L, CD137-L, OX40-L, CD27-L, and EGFR on breast cancer cells. Well-characterized pre-clinical heating systems are mandatory to screen the immune phenotype of tumor cells in clinically relevant settings to define immune matrices for therapy adaption.
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http://dx.doi.org/10.3390/cancers12051082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281749PMC
April 2020

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis.

Nat Commun 2020 04 24;11(1):1995. Epub 2020 Apr 24.

Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.

Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.
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http://dx.doi.org/10.1038/s41467-020-15831-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181728PMC
April 2020

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death.

J Immunother Cancer 2020 03;8(1)

Program of Immunology and Immunotherapy, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain.

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
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http://dx.doi.org/10.1136/jitc-2019-000337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064135PMC
March 2020

Editorial: Radioimmunotherapy-Translational Opportunities and Challenges.

Front Oncol 2020 21;10:190. Epub 2020 Feb 21.

Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany.

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http://dx.doi.org/10.3389/fonc.2020.00190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046688PMC
February 2020

Olanzapine combined with 5-hydroxytryptamine type 3 receptor antagonist (5-HT3 RA) plus dexamethasone for prevention and treatment of chemotherapy-induced nausea and vomiting in high and moderate emetogenic chemotherapy: a systematic review and meta-analysis of randomised controlled trials.

ESMO Open 2020 02;5(1)

Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany

We performed a pooled analysis to evaluate the efficacy and adverse events (AEs) of olanzapine combined with dexamethasone plus 5-hydroxytryptamine type 3 receptor antagonist (5-HT3 RA) compared with 5-HT3 RA plus dexamethasone for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in high and moderate emetogenic chemotherapy based on randomised controlled trials (RCTs). PubMed, EMBASE, Web of Science, the Cochrane Library, China Biomedical Literature database (CBM), WanFang Database, China National Knowledge Infrastructure (CNKI), and Chinese Science and Technology Periodical Database (VIP) (from their inception to April 2019) were searched to capture relevant articles. Relative risk with 95% confidence intervals for CINV and AEs were all extracted or calculated. Eleven studies with 1107 cancer patients were involved in this review. The pooled RR of delayed CINV (RR 0.50, 95% CI 0.38 to 0.66; p<0.01) were significantly decreased in the olanzapine group. The occurrence of insomnia was also statistically decreased, as was the rate of acute CINV (RR 0.60, 95% CI 0.48 to 0.75; p<0.01). However, only the percentages of CINV III and CINV IV were significantly decreased in the acute and delayed phases. Subgroup analysis demonstrated that the efficacy was not statistically significantly different between 5 mg and 10 mg olanzapine. Olanzapine significantly decreased the occurrence of CINV III and IV and insomnia in high and moderately emetogenic chemotherapy. Compared with 10 mg per day, 5 mg oral olanzapine may be more appropriate for patients with cancer.
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http://dx.doi.org/10.1136/esmoopen-2019-000621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046384PMC
February 2020

Early Mortality of Brain Cancer Patients and its Connection to Cytomegalovirus Reactivation During Radiochemotherapy.

Clin Cancer Res 2020 07 14;26(13):3259-3270. Epub 2020 Feb 14.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Purpose: If routine diagnostics are inconclusive, neurologic deterioration and death of patients with brain cancer are attributed to tumor or therapy. Therefore, diagnosing symptoms of encephalopathy caused by human cytomegalovirus (HCMV) reactivation remains uncommon. We investigated the role of HCMV reactivation in neurologic decline and clinical outcome after the start of radiochemotherapy.

Experimental Design: HCMV analyses and extended MRI studies including additional independent retrospective neuroradiologic evaluation were performed at predetermined intervals and in case of sudden neurologic decline for 118 adult patients: 63 histologically proven high-grade gliomas, 55 with brain metastases. Immunophenotyping from simultaneously taken whole-blood samples was carried out to detect immune cells serving as prognostic marker for HCMV-associated complications. Symptomatic viremia and overall survival (OS) were the endpoints.

Results: Twenty-four percent (28/118) of all patients (12/44 glioblastoma, 3/13 anaplastic astrocytoma; 8/31 non-small cell lung cancer (NSCLC), 13/24 other brain metastases) developed HCMV-viremia during or within 4 weeks after radiotherapy; 21 of 28 patients experienced concurrent major neurologic decline, reversible by antiviral treatment. Identified by immunophenotyping, pretherapeutically low basophil counts predicted a high-risk for HCMV-associated encephalopathy (glioblastoma: = 0.002, NSCLC: = 0.02). Median OS was substantially reduced after HCMV-associated encephalopathy without MRI signs of tumor progression [glioblastoma: 99 vs. 570 days (calculated 1-year OS: 22% vs. 69%; = 0.01) and NSCLC: 47 vs. 219 days (calculated 1-year OS: 0% vs. 32%; = 0.02)].

Conclusions: For patients with brain cancer, HCMV reactivation after the start of radiochemotherapy is a frequent risk for cognitively detrimental but treatable encephalopathy and premature death. Routinely performed HCMV diagnostics, assessing basophil counts and study-based anti-viral regimens, are necessary to combat this hidden threat..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3195DOI Listing
July 2020

[Promising results of the combination of radiotherapy and pembrolizumab in metastatic NSCLC].

Strahlenther Onkol 2020 03;196(3):289-292

Universitäts-Strahlenklinik Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstraße 27, 91054, Erlangen, Deutschland.

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http://dx.doi.org/10.1007/s00066-019-01573-zDOI Listing
March 2020

Analysis of the immune status from peripheral whole blood with a single-tube multicolor flow cytometry assay.

Methods Enzymol 2020 4;632:389-415. Epub 2019 Apr 4.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Supplementation of standard cancer therapies (radiotherapy, chemotherapy, surgery) with immunotherapies has revolutionized cancer treatment. In order to include recent improvements of multimodal therapies into clinical routine, knowledge about the immune status, the immune dynamics and the detailed composition and activation of patient's immune system is required. The here presented single-tube multicolor flow cytometry assay allows the discrimination of 20 clinically relevant immune cell subsets and their activation status in peripheral whole blood. It includes 15 different antibodies and can be established on a common 3 laser and 10 color flow-cytometer. Furthermore, this assay is easy to set-up and to perform as well as fast with only 40min of sample preparation time. Moreover, only 100μL of whole blood are sufficient for this precise determination of the individual immune status. It is already applied in translational programs of clinical studies and trials and can further be adapted for future ones.
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http://dx.doi.org/10.1016/bs.mie.2019.03.003DOI Listing
December 2020

Immune biological rationales for the design of combined radio- and immunotherapies.

Cancer Immunol Immunother 2020 Feb 18;69(2):293-306. Epub 2020 Jan 18.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Universitätsstraße 27, 91054, Erlangen, Germany.

Cancer immunotherapies are promising treatments for many forms of cancer. Nevertheless, the response rates to, e.g., immune checkpoint inhibitors (ICI), are still in low double-digit percentage. This calls for further therapy optimization that should take into account combination of immunotherapies with classical tumor therapies such as radiotherapy. By designing multimodal approaches, immune modulatory properties of certain radiation schemes, additional immune modulation by immunotherapy with ICI and hyperthermia, as well as patient stratification based on genetic and immune constitutions have to be considered. In this context, both the tumor and its microenvironment including cells of the innate and adaptive immune system have to be viewed in synopsis. Knowledge of immune activation and immune suppression by radiation is the basis for well-elaborated addition of certain immunotherapies. In this review, the focus is set on additional immune stimulation by hyperthermia and restoration of an immune response by ICI. The impact of radiation dose and fractionation on immune modulation in multimodal settings has to be considered, as the dynamics of the immune response and the timing between radiotherapy and immunotherapy. Another big challenge is the patient stratification that should be based on matrices of biomarkers, taking into account genetics, proteomics, radiomics, and "immunomics". One key aim is to turn immunological "cold" tumors into "hot" tumors, and to eliminate barriers of immune-suppressed or immune-excluded tumors. Comprehensive knowledge of immune alterations induced by radiation and immunotherapy when being applied together should be utilized for patient-adapted treatment planning and testing of innovative tumor therapies within clinical trials.
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http://dx.doi.org/10.1007/s00262-019-02460-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000501PMC
February 2020

Development and Validation of an RNA-Seq-Based Prognostic Signature in Neuroblastoma.

Front Oncol 2019 4;9:1361. Epub 2019 Dec 4.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany.

The stratification of neuroblastoma (NBL) prognosis remains difficult. RNA-based signatures might be able to predict prognosis, but independent cross-platform validation is still rare. RNA-Seq-based profiles from NBL patients were acquired and then analyzed. The RNA-Seq prognostic index (RPI) and the clinically adjusted RPI (RCPI) were successively established in the training cohort (TARGET-NBL) and then verified in the validation cohort (GSE62564). Survival prediction was assessed using a time-dependent receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). Functional enrichment analysis of the genes was conducted using bioinformatics methods. In the training cohort, 10 gene pairs were eventually integrated into the RPI. In both cohorts, the high-risk group had poor overall survival (OS) ( < 0.001 and < 0.001, respectively) and favorable event-free survival (EFS) ( = 0.00032 and = 0.06, respectively). ROC curve analysis also showed that the RPI predicted OS (60 month AUC values of 0.718 and 0.593, respectively) and EFS (60 month AUC values of 0.627 and 0.852, respectively) well in both the training and validation cohorts. Clinicopathological indicators associated with prognosis in the univariate and multivariate regression analyses were identified and added to the RPI to form the RCPI. The RCPI was also used to divide populations into different risk groups, and the high-risk group had poor OS ( < 0.001 and < 0.001, respectively) and EFS ( < 0.05 and < 0.05, respectively). Finally, the RCPI had higher accuracy than the RPI for the prediction of OS (60 month AUC values of 0.730 and 0.852, respectively) and EFS (60 month AUC values of 0.663 and 0.763, respectively) in both the training and validation cohorts. Moreover, these differentially expressed genes may be involved in certain NBL-related events. The RCPI could reliably categorize NBL patients based on different risks of death.
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http://dx.doi.org/10.3389/fonc.2019.01361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904333PMC
December 2019

Tumor Cell-Based Vaccine Generated With High Hydrostatic Pressure Synergizes With Radiotherapy by Generating a Favorable Anti-tumor Immune Microenvironment.

Front Oncol 2019 28;9:805. Epub 2019 Aug 28.

Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.

Dendritic cell (DC)-based vaccines pulsed with high hydrostatic pressure (HHP)-inactivated tumor cells have been demonstrated to be a promising immunotherapy for solid tumors. We focused on sole injection of tumor cells that were inactivated by HHP and their combination with local radiotherapy (RTx) for induction of anti-tumor immune responses. HHP-treatment of tumor cells resulted in pre-dominantly necrotic cells with degraded DNA. We confirmed that treatments at 200 MPa or higher completely inhibited the formation of tumor cell colonies . No tumor growth was seen after injection of HHP-treated tumor cells. Single vaccination with HHP-killed tumor cells combined with local RTx significantly retarded tumor growth and improved the survival as shown in B16-F10 and CT26 tumor models. In B16-F10 tumors that were irradiated with 2 × 5Gy and vaccinated once with HHP-killed tumor cells, the amount of natural killer (NK) cells, monocytes/macrophages, CD4+ T cells and NKT cells was significantly increased, while the amount of B cells was significantly decreased. In both models, a trend of increased CD8+ T cell infiltration was observed. Generally, in irradiated tumors high amounts of CD4+ and CD8+ T cells expressing PD-1 were found. We conclude that HHP generates inactivated tumor cells that can be used as a tumor vaccine. Moreover, we show for the first time that tumor cell-based vaccine acts synergistically with RTx to significantly retard tumor growth by generating a favorable anti-tumor immune microenvironment.
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http://dx.doi.org/10.3389/fonc.2019.00805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722191PMC
August 2019

Low-Dose Irradiation Differentially Impacts Macrophage Phenotype in Dependence of Fibroblast-Like Synoviocytes and Radiation Dose.

J Immunol Res 2019 14;2019:3161750. Epub 2019 Aug 14.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease whose main hallmark is inflammation and destruction of the joints. Two cell types within the synovium that play an important role in RA are fibroblast-like synoviocytes (FLS) and macrophages. The latter innate immune cells show a high plasticity in their phenotype and are central in inflammatory processes. Low-dose radiotherapy (LD-RT) with particularly a single dose of 0.5 Gy has been demonstrated to have a positive impact on pain, inflammation, and bone in inflamed joints. We now examined for the first time how LD-RT influences FLS and bone marrow-derived macrophages in co-culture systems of an experimental model of RA to reveal further mechanisms of immune modulatory effects of low and intermediate dose of ionizing radiation. For this, the bone marrow of h tg mice was differentiated either with cytokines to obtain key macrophage phenotypes (M0, M1, and M2) or with supernatants (SN) of untreated or irradiated FLS. Flow cytometry analyses were used to analyse the impact of radiation (0.1, 0.5, 1.0, and 2.0 Gy) on the phenotype of macrophages in the presence or absence of SN of FLS. LD-RT had no impact on cytokine-mediated macrophage polarization in M0, M1, or M2 macrophages. However, SN of irradiated FLS particularly reduced CD206 expression on macrophages. Macrophage phenotype was stable when being in contact with SN of nonirradiated FLS, but significantly increased surface expression of CD206 and slightly decreased CD80 and CD86 expression were observed when macrophage themselves were irradiated with 0.5 Gy under these microenvironmental conditions, again highlighting discontinuous dose dependencies in the low and intermediate dose range. One can conclude that FLS-dependent microenvironmental conditions have a slight influence on the modulation of macrophage phenotype under radiation exposure conditions. Future studies are needed to reveal the impact of radiation exposure on the functions of treated macrophages under such microenvironmental conditions.
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http://dx.doi.org/10.1155/2019/3161750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710796PMC
January 2020

Is it time to redefine the role of low-dose radiotherapy for benign disease?

Ann Rheum Dis 2020 03 21;79(3):e34. Epub 2018 Dec 21.

Department of Radiation Oncology, Hospital Universitari Sant Joan de Reus, University of Rovira i Virgili, Tarragona, Spain

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http://dx.doi.org/10.1136/annrheumdis-2018-214873DOI Listing
March 2020

Low-dose radiotherapy: Mayday, mayday. We've been hit!

Strahlenther Onkol 2019 04 18;195(4):285-288. Epub 2018 Dec 18.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Universitätsstr. 27, 91054, Erlangen, Germany.

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http://dx.doi.org/10.1007/s00066-018-1412-1DOI Listing
April 2019