RESUMO
The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.
Assuntos
Neoplasias , Radioterapia , Microambiente Tumoral , Humanos , Neoplasias/radioterapia , Neoplasias/imunologia , Neoplasias/terapia , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação , Animais , Radioterapia/métodos , Imunidade Inata/efeitos da radiação , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/imunologia , Imunidade AdaptativaRESUMO
The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in innate immune responses to viral infection and inhibition of autoimmunity. Recent studies have suggested that micronuclei formed by genotoxic stress can activate innate immune signaling via the cGAS-STING pathway. Here, we investigated cGAS localization, activation, and downstream signaling from micronuclei induced by ionizing radiation, replication stress, and chromosome segregation errors. Although cGAS localized to ruptured micronuclei via binding to self-DNA, we failed to observe cGAS activation; cGAMP production; downstream phosphorylation of STING, TBK1, or IRF3; nuclear accumulation of IRF3; or expression of interferon-stimulated genes. Failure to activate the cGAS-STING pathway was observed across primary and immortalized cell lines, which retained the ability to activate the cGAS-STING pathway in response to dsDNA or modified vaccinia virus infection. We provide evidence that micronuclei formed by genotoxic insults contain histone-bound self-DNA, which we show is inhibitory to cGAS activation in cells.
Assuntos
Segregação de Cromossomos , Proteínas de Membrana , Micronúcleos com Defeito Cromossômico , Nucleotídeos Cíclicos , Nucleotidiltransferases , Transdução de Sinais , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Humanos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Micronúcleos com Defeito Cromossômico/efeitos da radiação , Nucleotídeos Cíclicos/metabolismo , Fosforilação , Replicação do DNA/efeitos da radiação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 3 de Interferon/genética , Imunidade Inata/efeitos da radiação , Dano ao DNA , Células HEK293 , Animais , Radiação Ionizante , Células HeLaRESUMO
Mitochondrial antiviral signaling (MAVS) protein mediates innate antiviral responses, including responses to certain coronaviruses such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We have previously shown that ultraviolet-A (UVA) therapy can prevent virus-induced cell death in human ciliated tracheal epithelial cells (HTEpC) infected with coronavirus-229E (CoV-229E), and results in increased intracellular levels of MAVS. In this study, we explored the mechanisms by which UVA light can activate MAVS, and whether local UVA light application can activate MAVS at locations distant from the light source (e.g. via cell-to-cell communication). MAVS levels were compared in HTEpC exposed to 2 mW/cm2 narrow band (NB)-UVA for 20 min and in unexposed controls at 30-40% and at 100% confluency, and in unexposed HTEpC treated with supernatants or lysates from UVA-exposed cells or from unexposed controls. MAVS was also assessed in different sections of confluent monolayer plates where only one section was exposed to NB-UVA. Our results showed that UVA increases the expression of MAVS protein. Further, cells in a confluent monolayer exposed to UVA conferred an elevation in MAVS in cells adjacent to the exposed section, and also in cells in the most distant sections which were not exposed to UVA. In this study, human ciliated tracheal epithelial cells exposed to UVA demonstrate increased MAVS protein, and also appear to transmit this influence to confluent cells not exposed to UVA, likely via cell-cell signaling.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/efeitos da radiação , Raios Ultravioleta , Proteínas Adaptadoras de Transdução de Sinal/imunologia , COVID-19/imunologia , COVID-19/radioterapia , COVID-19/virologia , Comunicação Celular/imunologia , Comunicação Celular/efeitos da radiação , Células Cultivadas , Células Epiteliais/imunologia , Células Epiteliais/efeitos da radiação , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/efeitos da radiação , Humanos , Imunidade Inata/efeitos da radiação , Fotobiologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiação , Traqueia/citologia , Terapia UltravioletaRESUMO
Radiation and bacillus Calmette-Guérin (BCG) instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response; however, comparison of STING pathway molecules and the immune landscape following treatment in urothelial carcinoma has not been performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response. Mice were exposed to the oral carcinogen, BBN, for 12 weeks prior to treatment with a single 15 Gy dose of radiation or three intravesical instillations of BCG (1 × 108 CFU). At sacrifice, tumors were staged by a urologic pathologist and effects of therapy on the immune microenvironment were measured using the NanoString Myeloid Innate Immunity Panel and immunohistochemistry. Clinical relevance was established by measuring immune biomarker expression of cGAS and STING on a human tissue microarray consisting of BCG-treated non-muscle-invasive urothelial carcinomas. BCG instillations in the murine model elevated STING and downstream STING-induced interferon and pro-inflammatory molecules, intratumoral M1 macrophage and T-cell accumulation, and complete tumor eradication. In contrast, radiotherapy caused no changes in STING pathway or innate immune gene expression; rather, it induced M2 macrophage accumulation and elevated FoxP3 expression characteristic of immunosuppression. In human non-muscle-invasive bladder cancer, STING protein expression was elevated at baseline in patients who responded to BCG therapy and increased further after BCG therapy. Overall, these results show that STING pathway activation plays a key role in effective BCG-induced immune response and strongly indicate that the effects of BCG on the bladder cancer immune microenvironment are more beneficial than those induced by radiation. © 2021 The Pathological Society of Great Britain and Ireland.
Assuntos
Antineoplásicos/administração & dosagem , Vacina BCG/administração & dosagem , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/efeitos da radiação , Imunoterapia , Proteínas de Membrana/imunologia , Doses de Radiação , Neoplasias da Bexiga Urinária/terapia , Urotélio/efeitos dos fármacos , Urotélio/efeitos da radiação , Administração Intravesical , Animais , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/efeitos da radiação , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/efeitos da radiação , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/efeitos da radiação , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Urotélio/imunologia , Urotélio/metabolismoRESUMO
Microglia, the innate immune cells of the central nervous system, play a pivotal role in the modulation of neuroinflammation. Neuroinflammation has been implicated in many diseases of the CNS, including Alzheimer's disease and Parkinson's disease. It is well documented that microglial activation, initiated by a variety of stressors, can trigger a potentially destructive neuroinflammatory response via the release of pro-inflammatory molecules, and reactive oxygen and nitrogen species. However, the potential anti-inflammatory and neuroprotective effects that microglia are also thought to exhibit have been under-investigated. The application of ionising radiation at different doses and dose schedules may reveal novel methods for the control of microglial response to stressors, potentially highlighting avenues for treatment of neuroinflammation associated CNS disorders, such as Alzheimer's disease and Parkinson's disease. There remains a need to characterise the response of microglia to radiation, particularly low dose ionising radiation.
Assuntos
Mediadores da Inflamação/metabolismo , Microglia/efeitos da radiação , Doenças Neurodegenerativas/radioterapia , Neuroimunomodulação/efeitos da radiação , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Relação Dose-Resposta à Radiação , Humanos , Imunidade Inata/efeitos da radiação , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Estresse Nitrosativo/efeitos da radiação , Estresse Oxidativo/efeitos da radiação , Fenótipo , Receptores de GABA/metabolismoRESUMO
PURPOSE: We examined how radiation dose per fraction (DPF) and total dose, as represented by biological effective dose (BED), can independently and differentially affect the immunomodulatory capacity of radiation therapy (RT). METHODS AND MATERIALS: AT3-OVA mammary and MC38 colorectal tumors in C57BL/6 mice were irradiated with rationally selected dose-fractionation schedules, alone or with immune-modulating or -depleting agents. Tumor growth was monitored as a readout of therapeutic response. Flow cytometry and RNA sequencing of mouse tumors and analysis of transcriptomic data sets from irradiated human cancers were used to examine the immunomodulatory effects of the different radiation schedules. RESULTS: In AT3-OVA tumors, radiation DPF rather than BED determined the ability of RT to evoke local antitumor CD8+ T cell responses and synergize with anti-PD-1 therapy. Natural killer cell-mediated control of irradiated tumors was more sensitive to radiation BED. Radiation-induced regulatory T cell (Treg) responses, which were detected in both mouse and human tumors, were a major factor underlying the differential activation of adaptive immunity by radiation DPF and the activity of natural killer cells during the early phase of response to RT. Targeted inhibition of Treg responses within irradiated tumors rescued and enhanced local tumor control by RT and permitted the generation of abscopal and immunologic memory responses, irrespective of radiation schedule. MC38 tumors did not support the induction of an amplified Treg response to RT and were highly vulnerable to its immunoadjuvant effects. CONCLUSIONS: Local radiation-induced Treg responses are influenced by radiation schedule and tumor type and are a critical determinant of the immunoadjuvant potential of RT and its ability to synergize with T cell-targeted immunotherapy.
Assuntos
Fracionamento da Dose de Radiação , Neoplasias Experimentais/radioterapia , Linfócitos T Reguladores/imunologia , Imunidade Adaptativa/efeitos da radiação , Animais , Linfócitos T CD8-Positivos/imunologia , Feminino , Imunidade Inata/efeitos da radiação , Imunomodulação , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologiaRESUMO
PURPOSE: Radiation therapy, which is vital for the treatment of primary liver cancer, comes with unavoidable liver injury, which limits its implementation. N6-methyladenosine (m6A) methylation is involved in many molecular functions. However, its role in radiation-induced liver diseases (RILD) remains unknown. Herein, we investigate the role of m6A methylation in RILD. METHODS AND MATERIALS: Methylated RNA-immunoprecipitation sequencing and RNA transcriptome sequencing were used to reveal the methylation pattern of human hepatic stellate cells (HSCs) exposed to irradiation. C3H/HeN mice and stimulator of interferon genes (STING)-deficient mice underwent x-ray irradiation of 24 Gy in 3 fractions. The m6A methylation of the high-mobility group box 1 (HMGB1) transcript was validated using methylated RNA immunoprecipitation, RNA immunoprecipitation, luciferase assays, and a messenger RNA decay assay. RESULTS: Human hepatic stellate cells showed significant differences in methylation patterns after 8 Gy of x-ray irradiation. Irradiation recruited AlkB homolog 5 (ALKBH5) to demethylate m6A residues in the 3' untranslated region of HMGB1, which resulted in the activation of STING-interferon regulatory factor 3 signaling. Changes in the transcription of the 3' untranslated region of HMGB1 occurred after the knockdown of ALKBH5, which were eliminated after m6A residue mutation. Strikingly, ALKBH5 deficiency or HMGB1 silencing both attenuated type I interferon production and decreased hepatocyte apoptosis. In vivo depletion of ALKBH5 abolished the upregulation of HMGB1-mediated STING signaling and decreased liver inflammation, which was consistent with STING-/- mice treated with irradiation. Notably, YTHDF2 (m6A reader protein) directly bound to HMGB1 m6A-modified sites and promoted its degradation. CONCLUSIONS: ALKBH5-dependent HMGB1 expression mediates STING-interferon regulatory factor 3 innate immune response in RILD.
Assuntos
Homólogo AlkB 5 da RNA Desmetilase/fisiologia , Proteína HMGB1/fisiologia , Células Estreladas do Fígado/efeitos da radiação , Imunidade Inata/efeitos da radiação , Hepatopatias/etiologia , Neoplasias Hepáticas/radioterapia , Proteínas de Membrana/fisiologia , Animais , Proteína HMGB1/genética , Humanos , Interferon Tipo I/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Proteínas de Ligação a RNA/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has become pandemic on March 11th, 2020. COVID-19 has a range of symptoms that includes fever, fatigue, dry cough, aches, and labored breathing to acute respiratory distress and possibly death. Health systems and hospitals have been completely rearranged since March 2020 in order to limit the high rate of virus spreading. Hence, a great debate on deferrable visits and treatments including phototherapy for skin diseases is developing. In particular, as regards phototherapy very few data are currently available regarding the chance to continue it, even if it may be a useful resource for treating numerous dermatological patients. However, phototherapy has an immunosuppressive action possibly facilitating virus infection. In the context of COVID-19 infection risk it is important to pointed out whether sunlight, phototherapy and in particular ultraviolet radiation (UV-R) constitute or not a risk for patients. In this review we aimed to focus on the relationship between UV-R, sunlight, phototherapy, and viral infections particularly focusing on COVID-19.
Assuntos
COVID-19/epidemiologia , Pandemias , SARS-CoV-2/efeitos da radiação , Luz Solar , Raios Ultravioleta , Vitamina D/fisiologia , Imunidade Adaptativa/efeitos da radiação , Animais , Peptídeos Catiônicos Antimicrobianos/biossíntese , Peptídeos Catiônicos Antimicrobianos/fisiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Imunidade Inata/efeitos da radiação , Terapia de Imunossupressão , Interleucina-6/sangue , Moléculas com Motivos Associados a Patógenos , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Dermatopatias/radioterapia , Luz Solar/efeitos adversos , Receptores Toll-Like/fisiologia , Raios Ultravioleta/efeitos adversos , Terapia Ultravioleta/efeitos adversos , Vírus/efeitos da radiação , Vitamina D/biossíntese , Vitamina D/uso terapêutico , CatelicidinasRESUMO
Zinc oxide nanoparticles (ZnO-NPs) are widely used in almost every area of life. Therefore, exposure to them is unavoidable, which makes it necessary to assess their safety for humans. This paper aims to determine toxicity of ZnO-NPs of two diameters toward human immune cells responsible for: innate response (U-937 and HL-60) and acquired response (COLO-720L and HUT-78). Mitochondrial activity, membrane integrity, degree of cellular lipid oxidation, induction of inflammation, and activation of the apoptosis pathway were evaluated to determine differences in cellular response to the tested nanoparticles. ZnO-NPs with a diameter of 100 and 130 nm cause significant cell mortality at 25 and 12 mg/L, respectively. Mitochondrial damage leads to the activation of the caspase cascade and, consequently, to cell apoptosis. ZnO-NPs also cause peroxidation of membrane lipids. Due to the photocatalytic properties of ZnO-NPs, the effect of ultraviolet (UV) irradiation on the degree of their toxicity was also investigated. However, UV irradiation enhances the toxic effect of nanoparticles mainly by weakening the cell's defense capabilities. ZnO-NPs are cytotoxic to human immune system, and they may cause both long-term and short-term negative effects.
Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Óxido de Zinco/toxicidade , Imunidade Adaptativa/efeitos da radiação , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/patologia , Humanos , Imunidade Celular/efeitos da radiação , Imunidade Inata/efeitos da radiação , Inflamação/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Raios UltravioletaRESUMO
Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS-STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS-STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer-highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS-STING signaling, deleterious effects associated with cGAS-STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS-STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.
Assuntos
Anormalidades Induzidas por Radiação/genética , Imunidade/genética , Proteínas de Membrana/genética , Neoplasias/genética , Nucleotidiltransferases/genética , Anormalidades Induzidas por Radiação/imunologia , Anormalidades Induzidas por Radiação/patologia , Dano ao DNA/imunologia , Dano ao DNA/efeitos da radiação , Humanos , Imunidade/imunologia , Imunidade/efeitos da radiação , Imunidade Inata/efeitos da radiação , Proteínas de Membrana/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/radioterapia , Nucleotidiltransferases/imunologia , Transdução de Sinais/efeitos da radiaçãoRESUMO
Abscopal effects are an important aspect of targeted radiation therapy due to their implication in normal tissue toxicity from chronic inflammatory responses and mutagenesis. Gene expression can be used to determine abscopal effects at the molecular level. Synchrotron microbeam radiation therapy utilizing high-intensity X rays collimated into planar microbeams is a promising cancer treatment due to its reported ability to ablate tumors with less damage to normal tissues compared to conventional broadbeam radiation therapy techniques. The low scatter of synchrotron radiation enables microbeams to be delivered to tissue effectively, and is also advantageous for out-of-field studies because there is minimal interference from scatter. Mouse legs were irradiated at a dose rate of 49 Gy/s and skin samples in the out-of-field areas were collected. The out-of-field skin showed an increase in Tnf expression and a decrease in Mdm2 expression, genes associated with inflammation and DNA damage. These expression effects from microbeam exposure were similar to those found with broadbeam exposure. In immune-deficient Ccl2 knockout mice, we identified a different gene expression profile which showed an early increase in Mdm2, Tgfb1, Tnf and Ccl22 expression in out-of-field skin that was not observed in the immune-proficient mice. Our results suggest that the innate immune system is involved in out-of-field tissue responses and alterations in the immune response may not eliminate abscopal effects, but could change them.
Assuntos
Dano ao DNA/genética , Expressão Gênica/efeitos da radiação , Imunidade Inata/efeitos da radiação , Síncrotrons , Animais , Quimiocina CCL2/genética , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
OBJECTIVE: To assess the role of CCR10 in innate lymphoid cells (ILCs) response in radiation-induced skin damage. MATERIAL AND METHODS: CCR10+/- and CCR10-/- mice were treated with either a single dose of 5 Gy or 5 Gy everyday for 6 days with a total dose of 30 Gy with X-ray. ILCs from the skin were isolated and analyzed by flow cytometry 3 and 10 days after irradiation. A mouse model of radio-dermatitis was used to assess the skin damage 10 days after 6 × 5 Gy irradiation. RESULTS: Skin ILCs were decreased in both CCR10+/- and CCR10-/- mice 3 days after single irradiation (p < .05). However, the skin inflammation disappeared and ILCs returned to normal levels 10 days after single irradiation. ILCs of both genotypes were also decreased after 6 × 5 Gy irradiation, but the percentage of skin ILCs in CCR10-/- mice was lower than that in CCR10+/- mice 10 days after irradiation. The immunohistochemistry results showed that CCR10-/- mice had more severe skin inflammation than CCR10+/- mice. CONCLUSION: CCR10-/- mice had lower percentages of ILCs and more skin damage than CCR10+/- mice after irradiation. These findings indicate that skin ILCs are regulated by CCR10, which might be a potential target for reducing the radio-dermatitis.
Assuntos
Imunidade Inata/efeitos da radiação , Linfócitos/efeitos da radiação , Receptores CCR10/metabolismo , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiação , Pele/efeitos da radiação , Animais , Genótipo , Camundongos , Camundongos Endogâmicos C57BL , Pele/citologia , Pele/imunologia , Pele/metabolismoRESUMO
Radiotherapy is a pivotal component in the curative treatment of patients with localised cancer and isolated metastasis, as well as being used as a palliative strategy for patients with disseminated disease. The clinical efficacy of radiotherapy has traditionally been attributed to the local effects of ionising radiation, which induces cell death by directly and indirectly inducing DNA damage, but substantial work has uncovered an unexpected and dual relationship between tumour irradiation and the host immune system. In clinical practice, it is, therefore, tempting to tailor immunotherapies with radiotherapy in order to synergise innate and adaptive immunity against cancer cells, as well as to bypass immune tolerance and exhaustion, with the aim of facilitating tumour regression. However, our understanding of how radiation impacts on immune system activation is still in its early stages, and concerns and challenges regarding therapeutic applications still need to be overcome. With the increasing use of immunotherapy and its common combination with ionising radiation, this review briefly delineates current knowledge about the non-targeted effects of radiotherapy, and aims to provide insights, at the preclinical level, into the mechanisms that are involved with the potential to yield clinically relevant combinatorial approaches of radiotherapy and immunotherapy.
Assuntos
Efeito Espectador , Neoplasias/radioterapia , Evasão Tumoral/efeitos da radiação , Imunidade Adaptativa/efeitos da radiação , Animais , Humanos , Imunidade Inata/efeitos da radiação , Neoplasias/imunologia , RadioimunoterapiaRESUMO
Vesicular stomatitis virus (VSV) expressing IFNß induces apoptosis in multiple tumor models while maintaining an excellent safety profile. VSV-IFNß is oncoselective due to permissive replication in cells with an altered IFN pathway. The human VSV-IFNß (hIFNß) vector is currently used in clinical trials as a standalone therapy; however, we hypothesized that oncolytic virotherapy might be more effective when used in combination with radiotherapy (RT). We investigated the synergistic effects of RT and VSV-hIFNß in the subcutaneous PC3 and orthotopic LNCaP prostate xenograft models and a syngeneic RM9 prostate tumor model. VSV-IFNß combined with RT amplified tumor killing for PC3 and LNCaP xenografts, and RM9 tumors. This was attributed to the induction of proapoptotic genes leading to increased VSV-IFNß infection and replication, VSV expression, and oncolysis. In the RM9 tumors, combination therapy resulted in a robust antitumor immune response. Treated RM9 tumor-bearing mice demonstrated an increase in CD8+ and CD4+ T-cell numbers, 100% resistance to tumor rechallenge, and reduced resistance to reimplantation challenge with CD8+ knockdown. RT enhanced the activity of VSV-mediated oncolysis via attenuation of the innate antiviral response, resulting in increased VSV replication and the generation of an adaptive immune response earmarked by an increase in CD8+ lymphocyte numbers and antitumor activity. Local tumor irradiation combined with VSV-IFNß affects tumor cell death through direct and systemic activity in conjunction with pronounced antitumor immunity. IMPLICATIONS: Radiotherapy enhances VSV-mediated oncolysis and anti-tumor immunity, indicating that the ombination has promise for very high risk prostate cancer.
Assuntos
Terapia Combinada/métodos , Imunidade Inata/efeitos da radiação , Interferon beta/genética , Neoplasias da Próstata/terapia , Vesiculovirus/fisiologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/efeitos da radiação , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Masculino , Camundongos , Terapia Viral Oncolítica , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Radioterapia , Vesiculovirus/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The anti-tumor activity of interferons (IFNs) was first appreciated about half a century ago, and IFN-α2 was the first cancer immunotherapy approved by the US Food and Drug Administration. Radiation therapy (RT), one of the pillars of cancer treatment, directly causes DNA damage, which can lead to senescence and cell death in tumor cells. In recent years, however, RT-induced immunomodulatory effects have been recognized to play an indispensable role in achieving the optimum therapeutic effect of RT. Increasing evidence indicates that RT enhances adaptive anti-tumor immunity by augmenting the innate immune sensing of tumors in a type I IFN-dependent matter. This review briefly introduces the role of type I interferon in cancer and the available evidence on the overall effects of RT on tumor immunity mediated via type I IFN. Recent advances in deciphering the molecular mechanisms underlying the induction of type I IFNs triggered by RT, their clinical implications, and therapeutic opportunities will be highlighted.
Assuntos
Imunoterapia/métodos , Interferon Tipo I/imunologia , Neoplasias/imunologia , Neoplasias/radioterapia , Imunidade Adaptativa/efeitos da radiação , Terapia Combinada , Humanos , Imunidade Inata/efeitos da radiação , Interferon Tipo I/farmacologiaRESUMO
A malignant tumor consists of malignant cells as well as a wide array of normal host tissues including stroma, vasculature, and immune infiltrate. The interaction between cancer and these host tissues is critical as these host tissues play a variety of roles in supporting or resisting disease progression. Radiotherapy (RT) has direct effects on malignant cells, but, also, critically important effects on these other components of the tumor microenvironment (TME). Given the growing role of immune checkpoint inhibitors and other immunotherapy strategies, understanding how RT affects the TME, particularly the immune compartment, is essential to advance RT in this new era of cancer therapy. The interactions between RT and the TME are complex, affecting the innate and adaptive arms of the immune system. RT can induce both proinflammatory effects and immune suppressive effects that can either promote or impede antitumor immunity. It is likely that the initial proinflammatory effects of RT eventually lead to rebound immune-suppression as chronic inflammation sets in. The exact kinetics and nature of how RT changes the TME likely depends on timing, dose, fractionation, site irradiated, and tumor type. With increased understanding of the effects of RT on the TME, in the future it is likely that we will be able to personalize RT by varying the dose, site, and timing of intervention to generate the desired response to partner with immunotherapy strategies.
Assuntos
Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/radioterapia , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação , Imunidade Adaptativa/efeitos da radiação , Humanos , Imunidade Inata/efeitos da radiaçãoRESUMO
The role of radiation therapy for cancer is evolving as its biologic effects on tumors becomes more clearly defined. Traditionally, radiobiology models dose-response curves based on direct cytocidal effects of radiation on tumor cells. However, a more dynamic picture is emerging of the impact of radiation on the tumor microenvironment and the patient's innate and adaptive immune system. Radiation produces damage associated molecular patterns that activate innate immune receptors leading to a cascade of downstream signals. These signals alter the tumor infiltrating immune population, modulate immune cell activation status, and enhance antigen presentation. The changes are conducive to an adaptive immune response with the generation of antitumor T cells. Early findings from clinical trials incorporating radiation and immune checkpoint inhibitors show promising synergy between the 2 modalities. As more data matures from ongoing trials, clinicians can refine new strategies for using radiation together with immunotherapy to achieve improved clinical outcomes.
Assuntos
Imunidade Adaptativa/efeitos da radiação , Imunidade Inata/efeitos da radiação , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/radioterapia , Microambiente Tumoral/efeitos da radiação , Terapia Combinada , Humanos , Microambiente Tumoral/imunologiaRESUMO
Functional circadian timekeeping is necessary for homeostatic control of the immune system and appropriate immune responsiveness. Disruption of natural light-dark cycles, through light at night (LAN), impairs innate and adaptive immune responses in nocturnal rodents. These altered immune responses are associated with disrupted endogenous gene transcriptional and endocrine cycles. However, few studies have addressed the multigenerational consequences of systemic circadian rhythm disruption. We hypothesized that parental exposure to dim LAN (dLAN) would alter innate immune and sickness responses to an endotoxin challenge in adult offspring gestated and reared in dark nights. Adult male and female Siberian hamsters were exposed to either dark nights (DARK) or dLAN (~5 lux) for 8 weeks, then paired, mated, and thereafter housed under dark nights. Maternal exposure to dLAN prior to conception impaired febrile responses and increased splenic il-1 production in response to LPS in male offspring. Paternal pre-conception dLAN dampened offspring tnf-α expression in the hypothalamus, reduced serum bactericidal capacity, and dark phase locomotor activity. These changes occurred despite offspring being conceived, gestated, and reared under standard dark night conditions. Overall, these data suggest that dLAN has intergenerational effects on innate immunity and sickness responses.
Assuntos
Ritmo Circadiano/imunologia , Imunidade Inata/efeitos da radiação , Luz/efeitos adversos , Exposição Materna/efeitos adversos , Exposição Paterna/efeitos adversos , Animais , Animais Recém-Nascidos , Ritmo Circadiano/efeitos da radiação , Feminino , Masculino , Modelos Animais , Phodopus , FotoperíodoRESUMO
In the study here, the potential applicability of KMRC011 - an agonist of toll-like receptor-5 - as a countermeasure for radiation toxicities was evaluated. Following a single 5.5 Gy total body irradiation (TBI, surface absorbed dose = 7 Gy) of Co60 γ-rays, mortality rates and degrees of pathological lesions that developed over 80 days were compared in monkeys that received TBI only and a group that was injected once with KMRC011 (10 µg/kg) after TBI. Compared to the TBI-only hosts (80%), the death rate was significantly improved by the use of KMRC011 (40%), all deaths in both groups occurred in the period from Days 19-24 post-TBI. Further analysis of monkeys that survived until the end of the experiment showed that AST and ALT levels were elevated only in the TBI group, and that radiation-induced tissue damage was alleviated by the KMRC011 injection. Additionally, expression of cell death-related proteins was lower in tissues from the KMRC011-treated hosts than in those in the TBI-only group. Other measured parameters, including body weight, food uptake, and hematological values did not significantly differ between the two groups over the entire period. The results of this study, thus demonstrate that KMRC011 could potentially be used as a medical countermeasure for the treatment of acute radiation exposure.
Assuntos
Fragmentos de Peptídeos/farmacologia , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/farmacologia , Receptor 5 Toll-Like/agonistas , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/efeitos da radiação , Injeções Intramusculares , Macaca fascicularis , Masculino , Fragmentos de Peptídeos/uso terapêutico , Lesões Experimentais por Radiação/imunologia , Protetores contra Radiação/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiação , Receptor 5 Toll-Like/metabolismo , Irradiação Corporal TotalRESUMO
The generation of DNA double-strand breaks has historically been taught as the mechanism through which radiotherapy kills cancer cells. Recently, radiation-induced cytosolic DNA release and activation of the cGAS/STING pathway, with ensuing induction of interferon secretion and immune activation, have been recognized as important mechanisms for radiation-mediated anti-tumor efficacy. Here we demonstrate that radiation-induced activation of endogenous retroviruses (ERVs) also plays a major role in regulating the anti-tumor immune response during irradiation. Radiation-induced ERV-associated dsRNA transcription and subsequent activation of the innate antiviral MDA5/MAVS/TBK1 pathway led to downstream transcription of interferon-stimulated genes. Additionally, genetic knockout of KAP1, a chromatin modulator responsible for suppressing ERV transcription sites within the genome, enhanced the effect of radiation-induced anti-tumor response in vivo in two different tumor models. This anti-tumor response was immune-mediated and required an intact host immune system. Our findings indicate that radiation-induced ERV-dsRNA expression and subsequent immune response play critical roles in clinical radiotherapy, and manipulation of epigenetic regulators and the dsRNA-sensing innate immunity pathway could be promising targets to enhance the efficacy of radiotherapy and cancer immunotherapy.