Immunomodulatory Effects of Radiotherapy

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.

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Characterisation of deubiquitylating enzymes in the cellular response to high-LET ionising radiation and complex DNA damage

10.1101/453118 ◽

2018 ◽

Author(s):

Rachel J. Carter ◽

Catherine M. Nickson ◽

James M. Thompson ◽

Andrzej Kacperek ◽

Mark A. Hill ◽

...

Keyword(s):

Dna Damage ◽

Cell Survival ◽

Cellular Response ◽

Cell Killing ◽

Dna Lesions ◽

Ionising Radiation ◽

X Rays ◽

High Let Radiation ◽

High Let ◽

Parp 1

AbstractPurposeIonising radiation, particular high linear energy transfer (LET) radiation, can induce complex DNA damage (CDD) where two or more DNA lesions are induced in close proximity which contributes significantly to the cell killing effects. However knowledge of the enzymes and mechanisms involved in co-ordinating the recognition and processing of CDD in cellular DNA are currently lacking.Methods and MaterialsAn siRNA screen of deubiquitylation enzymes was conducted in HeLa cells irradiated with high-LET -particles or protons, versus low-LET protons and x-rays, and cell survival monitored by clonogenic assays. Candidates whose depletion led to decreased cell survival specifically in response to high-LET radiation were validated in both HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells, and the association with CDD repair was confirmed by using an enzyme modified neutral comet assay.ResultsDepletion of USP6 decreased cell survival specifically following high-LET α-particles and protons, but not by low-LET protons or x-rays. USP6 depletion caused cell cycle arrest and a deficiency in CDD repair mediated through instability of poly(ADP-ribose) polymerase-1 (PARP-1). This phenotype was mimicked using the PARP inhibitor olaparib.ConclusionUSP6 controls cell survival in response to high-LET radiation by stabilising PARP-1 protein levels which is essential for CDD repair. We also describe synergy between CDD induced by high-LET protons and PARP inhibition in effective cancer cell killing.

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Clustered DNA Double-Strand Breaks: Biological Effects and Relevance to Cancer Radiotherapy

Genes ◽

10.3390/genes11010099 ◽

2020 ◽

Vol 11 (1) ◽

pp. 99 ◽

Cited By ~ 14

Author(s):

Jac A. Nickoloff ◽

Neelam Sharma ◽

Lynn Taylor

Keyword(s):

Dna Damage ◽

Dna Lesions ◽

Double Strand Breaks ◽

Single Strand ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

High Let Radiation ◽

High Let ◽

Radiation Induced ◽

Clustered Dna Damage

Cells manage to survive, thrive, and divide with high accuracy despite the constant threat of DNA damage. Cells have evolved with several systems that efficiently repair spontaneous, isolated DNA lesions with a high degree of accuracy. Ionizing radiation and a few radiomimetic chemicals can produce clustered DNA damage comprising complex arrangements of single-strand damage and DNA double-strand breaks (DSBs). There is substantial evidence that clustered DNA damage is more mutagenic and cytotoxic than isolated damage. Radiation-induced clustered DNA damage has proven difficult to study because the spectrum of induced lesions is very complex, and lesions are randomly distributed throughout the genome. Nonetheless, it is fairly well-established that radiation-induced clustered DNA damage, including non-DSB and DSB clustered lesions, are poorly repaired or fail to repair, accounting for the greater mutagenic and cytotoxic effects of clustered lesions compared to isolated lesions. High linear energy transfer (LET) charged particle radiation is more cytotoxic per unit dose than low LET radiation because high LET radiation produces more clustered DNA damage. Studies with I-SceI nuclease demonstrate that nuclease-induced DSB clusters are also cytotoxic, indicating that this cytotoxicity is independent of radiogenic lesions, including single-strand lesions and chemically “dirty” DSB ends. The poor repair of clustered DSBs at least in part reflects inhibition of canonical NHEJ by short DNA fragments. This shifts repair toward HR and perhaps alternative NHEJ, and can result in chromothripsis-mediated genome instability or cell death. These principals are important for cancer treatment by low and high LET radiation.

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Crocetin Mitigates Irradiation Injury in an In Vitro Model of the Pubertal Testis: Focus on Biological Effects and Molecular Mechanisms

Molecules ◽

10.3390/molecules26061676 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1676

Author(s):

Giulia Rossi ◽

Martina Placidi ◽

Chiara Castellini ◽

Francesco Rea ◽

Settimio D'Andrea ◽

...

Keyword(s):

In Vitro Model ◽

Molecular Mechanisms ◽

Biological Effects ◽

Cellular Damage ◽

X Rays ◽

Adolescent Cancer ◽

Radiation Induced ◽

Vitro Model ◽

Underlying Mechanisms

Infertility is a potential side effect of radiotherapy and significantly affects the quality of life for adolescent cancer survivors. Very few studies have addressed in pubertal models the mechanistic events that could be targeted to provide protection from gonadotoxicity and data on potential radioprotective treatments in this peculiar period of life are elusive. In this study, we utilized an in vitro model of the mouse pubertal testis to investigate the efficacy of crocetin to counteract ionizing radiation (IR)-induced injury and potential underlying mechanisms. Present experiments provide evidence that exposure of testis fragments from pubertal mice to 2 Gy X-rays induced extensive structural and cellular damage associated with overexpression of PARP1, PCNA, SOD2 and HuR and decreased levels of SIRT1 and catalase. A twenty-four hr exposure to 50 μM crocetin pre- and post-IR significantly reduced testis injury and modulated the response to DNA damage and oxidative stress. Nevertheless, crocetin treatment did not counteract the radiation-induced changes in the expression of SIRT1, p62 and LC3II. These results increase the knowledge of mechanisms underlying radiation damage in pubertal testis and establish the use of crocetin as a fertoprotective agent against IR deleterious effects in pubertal period.

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Alpha-Particle Exposure Induces Mainly Unstable Complex Chromosome Aberrations which do not Contribute to Radiation-Associated Cytogenetic Risk

Radiation Research ◽

10.1667/rade-21-00116.1 ◽

2021 ◽

Author(s):

C. Hartel ◽

E. Nasonova ◽

S. Ritter ◽

T. Friedrich

Keyword(s):

Ex Vivo ◽

Human Peripheral Blood ◽

Mitotic Cell ◽

Peripheral Blood Lymphocytes ◽

Small Scale ◽

X Rays ◽

Carcinogenic Effect ◽

High Let Radiation ◽

High Let ◽

Α Particles

The mechanism underlying the carcinogenic potential of α radiation is not fully understood, considering that cell inactivation (e.g., mitotic cell death) as a main consequence of exposure efficiently counteracts the spreading of heritable DNA damage. The aim of this study is to improve our understanding of the effectiveness of α particles in inducing different types of chromosomal aberrations, to determine the respective values of the relative biological effectiveness (RBE) and to interpret the results with respect to exposure risk. Human peripheral blood lymphocytes (PBLs) from a single donor were exposed ex vivo to doses of 0–6 Gy X rays or 0–2 Gy α particles. Cells were harvested at two different times after irradiation to account for the mitotic delay of heavily damaged cells, which is known to occur after exposure to high-LET radiation (including α particles). Analysis of the kinetics of cells reaching first or second (and higher) mitosis after irradiation and aberration data obtained by the multiplex fluorescence in situ hybridization (mFISH) technique are used to determine of the cytogenetic risk, i.e., the probability for transmissible aberrations in surviving lymphocytes. The analysis shows that the cytogenetic risk after α exposure is lower than after X rays. This indicates that the actually observed higher carcinogenic effect of α radiation is likely to stem from small scale mutations that are induced effectively by high-LET radiation but cannot be resolved by mFISH analysis.

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DIFFERENCES BETWEEN MAN AND MICE WITH RESPECT TO REPAIR KINETICS OF RADIATION-INDUCED DNA LESIONS, AFTER EXPOSURE TO BIOLOGICALLY RELEVANT DOSES OF X-RAYS

Radiation Research: A Twentieth-century Perspective ◽

10.1016/b978-0-12-168561-4.51038-6 ◽

1991 ◽

pp. 307

Author(s):

A.A.W.M. van Loon ◽

G.P. van der Schans ◽

P.H.M. Lohman

Keyword(s):

Dna Lesions ◽

X Rays ◽

Biologically Relevant ◽

Radiation Induced ◽

Kinetics Of

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High-LET radiation-induced aberrations in prematurely condensed G2 chromosomes of human fibroblasts

International Journal of Radiation Biology ◽

10.1080/09553000050050945 ◽

2000 ◽

Vol 76 (7) ◽

pp. 929-937 ◽

Cited By ~ 34

Author(s):

T. Kawata, E. Gotoh, M. Durante, H. Wu

Keyword(s):

Human Fibroblasts ◽

High Let Radiation ◽

High Let ◽

Radiation Induced

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Increased Hematopoietic Stem Cells/Hematopoietic Progenitor Cells Measured as Endogenous Spleen Colonies in Radiation-Induced Adaptive Response in Mice (Yonezawa Effect)

Dose-Response ◽

10.1177/1559325818790152 ◽

2018 ◽

Vol 16 (3) ◽

pp. 155932581879015 ◽

Cited By ~ 4

Author(s):

Bing Wang ◽

Kaoru Tanaka ◽

Yasuharu Ninomiya ◽

Kouichi Maruyama ◽

Guillaume Varès ◽

...

Keyword(s):

Bone Marrow ◽

Adaptive Response ◽

Underlying Mechanism ◽

Hematopoietic Progenitor Cells ◽

X Rays ◽

Hematopoietic Progenitor ◽

Hematopoietic Stem ◽

Different Types ◽

Radiation Induced

The existence of radiation-induced adaptive response (AR) was reported in varied biosystems. In mice, the first in vivo AR model was established using X-rays as both the priming and the challenge doses and rescue of bone marrow death as the end point. The underlying mechanism was due to the priming radiation-induced resistance in the blood-forming tissues. In a series of investigations, we further demonstrated the existence of AR using different types of ionizing radiation (IR) including low linear energy transfer (LET) X-rays and high LET heavy ion. In this article, we validated hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs) measured as endogenous colony-forming units-spleen (CFU-S) under AR inducible and uninducible conditions using combination of different types of IR. We confirmed the consistency of increased CFU-S number change with the AR inducible condition. These findings suggest that AR in mice induced by different types of IR would share at least in part a common underlying mechanism, the priming IR-induced resistance in the blood-forming tissues, which would lead to a protective effect on the HSCs/HPCs and play an important role in rescuing the animals from bone marrow death. These findings provide a new insight into the mechanistic study on AR in vivo.

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Protective Effects of p53 Regulatory Agents Against High-LET Radiation-Induced Injury in Mice

Frontiers in Public Health ◽

10.3389/fpubh.2020.601124 ◽

2020 ◽

Vol 8 ◽

Author(s):

Akinori Morita ◽

Bing Wang ◽

Kaoru Tanaka ◽

Takanori Katsube ◽

Masahiro Murakami ◽

...

Keyword(s):

Cell Death ◽

Radiation Injury ◽

Ion Irradiation ◽

Heavy Ion ◽

Protective Effects ◽

Iron Ion ◽

Normal Tissues ◽

High Let Radiation ◽

High Let ◽

Radiation Induced

Radiation damage to normal tissues is one of the most serious concerns in radiation therapy, and the tolerance dose of the normal tissues limits the therapeutic dose to the patients. p53 is well known as a transcription factor closely associated with radiation-induced cell death. We recently demonstrated the protective effects of several p53 regulatory agents against low-LET X- or γ-ray-induced damage. Although it was reported that high-LET heavy ion radiation (>85 keV/μm) could cause p53-independent cell death in some cancer cell lines, whether there is any radioprotective effect of the p53 regulatory agents against the high-LET radiation injury in vivo is still unclear. In the present study, we verified the efficacy of these agents on bone marrow and intestinal damages induced by high-LET heavy-ion irradiation in mice. We used a carbon-beam (14 keV/μm) that was shown to induce a p53-dependent effect and an iron-beam (189 keV/μm) that was shown to induce a p53-independent effect in a previous study. Vanadate significantly improved 60-day survival rate in mice treated with total-body carbon-ion (p < 0.0001) or iron-ion (p < 0.05) irradiation, indicating its effective protection of the hematopoietic system from radiation injury after high-LET irradiation over 85 keV/μm. 5CHQ also significantly increased the survival rate after abdominal carbon-ion (p < 0.02), but not iron-ion irradiation, suggesting the moderate relief of the intestinal damage. These results demonstrated the effectiveness of p53 regulators on acute radiation syndrome induced by high-LET radiation.

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