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Radiation in Multimodal Tumor Immune Therapies – Mechanisms and Application
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Radiation in Multimodal Tumor Immune Therapies – Mechanisms and Application

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 35904

Special Issue Editors

Prof. Dr. Udo S. Gaipl

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Guest Editor
Head of Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany
Interests: immune modulation by radiation; tumor immunology; hyperthermia; vaccination; osteoimmunological mechanisms of low-dose radiation therapy; translational immune monitoring; combined radio-immunotherapies; prognostic and predictive immune biomarkers
Special Issues, Collections and Topics in MDPI journals
Dr. Benjamin Frey

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Guest Editor
Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 27, 91054 Erlangen, Germany
Interests: radiotherapy; immunotherapy; vaccination; immune checkpoints; hyperthermia; tumor immunology; immunogenic cancer cell death; immunomonitoring; inflammatory and degenerative diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

After the great success of the special issue on “Partnership of Radiotherapy and Immunotherapy”, in this Issue, we will continue to focus on how radiation modulates the immune system, and thereby contributes to the induction of anti-tumor immune reactions, and/or creates a micro-environment that calls for the addition of distinct immune therapies. On the other hand, the modes of action of immunotherapies should be picked up and put in connection with radiation responses. In this context, stratification markers for a combination of radiotherapy and immunotherapy should be suggested, validated, and critically discussed. We are looking forward to receiving submissions about the basic science and translational workings of a immuno-oncology society.

With warm regards,

Prof. Dr. Udo S. Gaipl
Dr. Benjamin Frey
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Radiotherapy
  • DNA damage responses
  • Immunotherapy
  • Immune checkpoints
  • Vaccination
  • Cytokines
  • Adoptive immune cell transfer
  • Hyperthermia
  • Cancer
  • Biomarkers
  • Immune monitoring
  • Tumor mutational burden
  • HLA class II antigen-processing pathway

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Related Special Issue

Published Papers (7 papers)

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Editorial

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2 pages, 156 KiB  
Editorial
Editorial to Radiation in Multimodal Tumor Immune Therapies—Mechanisms and Application
by Benjamin Frey and Udo S. Gaipl
Int. J. Mol. Sci. 2021, 22(14), 7648; https://doi.org/10.3390/ijms22147648 - 17 Jul 2021
Viewed by 1470
Abstract
The understanding and the application of radiation-induced immune modulation has become more and more relevant in the therapy of malignant, but also benign diseases [...] Full article
(This article belongs to the Special Issue Radiation in Multimodal Tumor Immune Therapies – Mechanisms and Application)

Research

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14 pages, 1645 KiB  
Article
Tumors Resistant to Checkpoint Inhibitors Can Become Sensitive after Treatment with Vascular Disrupting Agents
by Michael R. Horsman, Thomas R. Wittenborn, Patricia S. Nielsen and Pernille B. Elming
Int. J. Mol. Sci. 2020, 21(13), 4778; https://doi.org/10.3390/ijms21134778 - 6 Jul 2020
Cited by 12 | Viewed by 2572
Abstract
Immune therapy improves cancer outcomes, yet many patients do not respond. This pre-clinical study investigated whether vascular disrupting agents (VDAs) could convert an immune unresponsive tumor into a responder. CDF1 mice, with 200 mm3 C3H mammary carcinomas in the right rear foot, [...] Read more.
Immune therapy improves cancer outcomes, yet many patients do not respond. This pre-clinical study investigated whether vascular disrupting agents (VDAs) could convert an immune unresponsive tumor into a responder. CDF1 mice, with 200 mm3 C3H mammary carcinomas in the right rear foot, were intraperitoneally injected with combretastatin A-4 phosphate (CA4P), its A-1 analogue OXi4503, and/or checkpoint inhibitors (anti-PD-1, PD-L1, or CTLA-4 antibodies), administered twice weekly for two weeks. Using the endpoint of tumor growth time (TGT5; time to reach five times the starting volume), we found that none of the checkpoint inhibitors (10 mg/kg) had any effect on TGT5 compared to untreated controls. However, CA4P (100 mg/kg) or OXi4503 (5–50 mg/kg) did significantly increase TGT5. This further significantly increased by combining the VDAs with checkpoint inhibitors, but was dependent on the VDA, drug dose, and inhibitor. For CA4P, a significant increase was found when CA4P (100 mg/kg) was combined with anti-PD-L1, but not with the other two checkpoint inhibitors. With OXi4503 (50 mg/kg), a significant enhancement occurred when combined with anti-PD-L1 or anti-CTLA-4, but not anti-PD-1. We observed no significant improvement with lower OXi4503 doses (5–25 mg/kg) and anti-CTLA-4, although 30% of tumors were controlled at the 25 mg/kg dose. Histological assessment of CD4/CD8 expression actually showed decreased levels up to 10 days after treatment with OXi4503 (50 mg/kg). Thus, the non-immunogenic C3H mammary carcinoma was unresponsive to checkpoint inhibitors, but became responsive in mice treated with VDAs, although the mechanism remains unclear. Full article
(This article belongs to the Special Issue Radiation in Multimodal Tumor Immune Therapies – Mechanisms and Application)
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19 pages, 5096 KiB  
Article
Sublethal Radiation Affects Antigen Processing and Presentation Genes to Enhance Immunogenicity of Cancer Cells
by Achamaporn Punnanitinont, Eric D. Kannisto, Junko Matsuzaki, Kunle Odunsi, Sai Yendamuri, Anurag K. Singh and Santosh K. Patnaik
Int. J. Mol. Sci. 2020, 21(7), 2573; https://doi.org/10.3390/ijms21072573 - 7 Apr 2020
Cited by 11 | Viewed by 4251
Abstract
While immunotherapy in cancer is designed to stimulate effector T cell response, tumor-associated antigens have to be presented on malignant cells at a sufficient level for recognition of cancer by T cells. Recent studies suggest that radiotherapy enhances the anti-cancer immune response and [...] Read more.
While immunotherapy in cancer is designed to stimulate effector T cell response, tumor-associated antigens have to be presented on malignant cells at a sufficient level for recognition of cancer by T cells. Recent studies suggest that radiotherapy enhances the anti-cancer immune response and also improves the efficacy of immunotherapy. To understand the molecular basis of such observations, we examined the effect of ionizing X-rays on tumor antigens and their presentation in a set of nine human cell lines representing cancers of the esophagus, lung, and head and neck. A single dose of 7.5 or 15 Gy radiation enhanced the New York esophageal squamous cell carcinoma 1 (NY-ESO-1) tumor-antigen-mediated recognition of cancer cells by NY-ESO-1-specific CD8+ T cells. Irradiation led to significant enlargement of live cells after four days, and microscopy and flow cytometry revealed multinucleation and polyploidy in the cells because of dysregulated mitosis, which was also revealed in RNA-sequencing-based transcriptome profiles of cells. Transcriptome analyses also showed that while radiation had no universal effect on genes encoding tumor antigens, it upregulated the expression of numerous genes involved in antigen processing and presentation pathways in all cell lines. This effect may explain the immunostimulatory role of cancer radiotherapy. Full article
(This article belongs to the Special Issue Radiation in Multimodal Tumor Immune Therapies – Mechanisms and Application)
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15 pages, 2488 KiB  
Article
Combination of Gas Plasma and Radiotherapy Has Immunostimulatory Potential and Additive Toxicity in Murine Melanoma Cells in Vitro
by Gabriella Pasqual-Melo, Sanjeev Kumar Sagwal, Eric Freund, Rajesh Kumar Gandhirajan, Benjamin Frey, Thomas von Woedtke, Udo Gaipl and Sander Bekeschus
Int. J. Mol. Sci. 2020, 21(4), 1379; https://doi.org/10.3390/ijms21041379 - 18 Feb 2020
Cited by 33 | Viewed by 3565
Abstract
Despite continuous advances in therapy, malignant melanoma is still among the deadliest types of cancer. At the same time, owing to its high plasticity and immunogenicity, melanoma is regarded as a model tumor entity when testing new treatment approaches. Cold physical plasma is [...] Read more.
Despite continuous advances in therapy, malignant melanoma is still among the deadliest types of cancer. At the same time, owing to its high plasticity and immunogenicity, melanoma is regarded as a model tumor entity when testing new treatment approaches. Cold physical plasma is a novel anticancer tool that utilizes a plethora of reactive oxygen species (ROS) being deposited on the target cells and tissues. To test whether plasma treatment would enhance the toxicity of an established antitumor therapy, ionizing radiation, we combined both physical treatment modalities targeting B16F10 murine melanoma cell in vitro. Repeated rather than single radiotherapy, in combination with gas plasma-introduced ROS, induced apoptosis and cell cycle arrest in an additive fashion. In tendency, gas plasma treatment sensitized the cells to subsequent radiotherapy rather than the other way around. This was concomitant with increased levels of TNFα, IL6, and GM-CSF in supernatants. Murine JAWS dendritic cells cultured in these supernatants showed an increased expression of cell surface activation markers, such as MHCII and CD83. For PD-L1 and PD-L2, increased expression was observed. Our results are the first to suggest an additive therapeutic effect of gas plasma and radiotherapy, and translational tumor models are needed to develop this concept further. Full article
(This article belongs to the Special Issue Radiation in Multimodal Tumor Immune Therapies – Mechanisms and Application)
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15 pages, 5087 KiB  
Article
N-Dihydrogalactochitosan Potentiates the Radiosensitivity of Liver Metastatic Tumor Cells Originated from Murine Breast Tumors
by Chung-Yih Wang, Chun-Yuan Chang, Chun-Yu Wang, Kaili Liu, Chia-Yun Kang, Yi-Jang Lee and Wei R. Chen
Int. J. Mol. Sci. 2019, 20(22), 5581; https://doi.org/10.3390/ijms20225581 - 8 Nov 2019
Cited by 5 | Viewed by 3110
Abstract
Radiation is a widely used therapeutic method for treating breast cancer. N-dihydrogalactochitosan (GC), a biocompatible immunostimulant, is known to enhance the effects of various treatment modalities in different tumor types. However, whether GC can enhance the radiosensitivity of cancer cells remains to [...] Read more.
Radiation is a widely used therapeutic method for treating breast cancer. N-dihydrogalactochitosan (GC), a biocompatible immunostimulant, is known to enhance the effects of various treatment modalities in different tumor types. However, whether GC can enhance the radiosensitivity of cancer cells remains to be explored. In this study, triple-negative murine 4T1 breast cancer cells transduced with multi-reporter genes were implanted in immunocompetent Balb/C mice to track, dissect, and identify liver-metastatic 4T1 cells. These cells expressed cancer stem cell (CSC) -related characteristics, including the ability to form spheroids, the expression of the CD44 marker, and the increase of protein stability. We then ex vivo investigated the potential effect of GC on the radiosensitivity of the liver-metastatic 4T1 breast cancer cells and compared the results to those of parental 4T1 cells subjected to the same treatment. The cells were irradiated with increased doses of X-rays with or without GC treatment. Colony formation assays were then performed to determine the survival fractions and radiosensitivity of these cells. We found that GC preferably increased the radiosensitivity of liver-metastatic 4T1 breast cancer cells rather than that of the parental cells. Additionally, the single-cell DNA electrophoresis assay (SCDEA) and γ-H2AX foci assay were performed to assess the level of double-stranded DNA breaks (DSBs). Compared to the parental cells, DNA damage was significantly increased in liver-metastatic 4T1 cells after they were treated with GC plus radiation. Further studies on apoptosis showed that this combination treatment increased the sub-G1 population of cells, but not caspase-3 cleavage, in liver-metastatic breast cancer cells. Taken together, the current data suggest that the synergistic effects of GC and irradiation might be used to enhance the efficacy of radiotherapy in treating metastatic tumors. Full article
(This article belongs to the Special Issue Radiation in Multimodal Tumor Immune Therapies – Mechanisms and Application)
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Review

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39 pages, 1686 KiB  
Review
Radon Exposure—Therapeutic Effect and Cancer Risk
by Andreas Maier, Julia Wiedemann, Felicitas Rapp, Franziska Papenfuß, Franz Rödel, Stephanie Hehlgans, Udo S. Gaipl, Gerhard Kraft, Claudia Fournier and Benjamin Frey
Int. J. Mol. Sci. 2021, 22(1), 316; https://doi.org/10.3390/ijms22010316 - 30 Dec 2020
Cited by 46 | Viewed by 14291
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Radiation in Multimodal Tumor Immune Therapies – Mechanisms and Application)
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29 pages, 3331 KiB  
Review
Immunomodulatory Effects of Radiotherapy
by Sharda Kumari, Shibani Mukherjee, Debapriya Sinha, Salim Abdisalaam, Sunil Krishnan and Aroumougame Asaithamby
Int. J. Mol. Sci. 2020, 21(21), 8151; https://doi.org/10.3390/ijms21218151 - 31 Oct 2020
Cited by 49 | Viewed by 5778
Abstract
Radiation therapy (RT), an integral component of curative treatment for many malignancies, can be administered via an increasing array of techniques. In this review, we summarize the properties and application of different types of RT, specifically, conventional therapy with x-rays, stereotactic body RT, [...] Read more.
Radiation therapy (RT), an integral component of curative treatment for many malignancies, can be administered via an increasing array of techniques. In this review, we summarize the properties and application of different types of RT, specifically, conventional therapy with x-rays, stereotactic body RT, and proton and carbon particle therapies. We highlight how low-linear energy transfer (LET) radiation induces simple DNA lesions that are efficiently repaired by cells, whereas high-LET radiation causes complex DNA lesions that are difficult to repair and that ultimately enhance cancer cell killing. Additionally, we discuss the immunogenicity of radiation-induced tumor death, elucidate the molecular mechanisms by which radiation mounts innate and adaptive immune responses and explore strategies by which we can increase the efficacy of these mechanisms. Understanding the mechanisms by which RT modulates immune signaling and the key players involved in modulating the RT-mediated immune response will help to improve therapeutic efficacy and to identify novel immunomodulatory drugs that will benefit cancer patients undergoing targeted RT. Full article
(This article belongs to the Special Issue Radiation in Multimodal Tumor Immune Therapies – Mechanisms and Application)
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