The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer.

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.

Inflammation and immunity in radiation damage to the gut mucosa.

Erythema was observed on the skin of the first patients treated with radiation therapy. It is in particular to reduce this erythema, one feature of tissue inflammation, that prescribed dose to the tumor site started to be fractionated. It is now well known that radiation exposure of normal tissues generates a sustained and apparently uncontrolled inflammatory process. Radiation-induced inflammation is always observed, often described, sometimes partly explained, but still today far from being completely understood. The thing with the gut and especially the gut mucosa is that it is at the frontier between the external milieu and the organism, is in contact with a plethora of commensal and foreign antigens, possesses a dense-associated lymphoid tissue, and is particularly radiation sensitive because of a high mucosal turnover rate. All these characteristics make the gut mucosa a strong responsive organ in terms of radiation-induced immunoinflammation. This paper will focus on what has been observed in the normal gut and what remains to be done concerning the immunoinflammatory response following localized radiation exposure.

[Autoimmune processes after long-term low-level exposure to electromagnetic fields (the results of an experiment). Part 5. Impact of the blood serum from rats exposed to low-level electromagnetic fields on pregnancy, foetus and offspring development of intact female rats].

This study evaluated possible adverse effects of injection of blood serum from rats exposed to microwaves at a power density of 500 microW/cm2 on pregnancy and foetal and offspring development in intact female rats. The study was performed with 59 pregnant Wistar rats. In utero mortality, embryo and foetal body weights and placenta weight were used for the evaluation of embryo and foetal development. Generally accepted integral and specific parameters were used for the evaluation of postnatal development of offspring during the first 30 days of life. It was shown that intra peritoneal injection of blood serum from IMF exposed rats (chronic 30-day RF exposure at 500 microW/cm2) to intact rats on the 10th day of pregnancy resulted in adverse effects on foetal and offspring development. Total mortality (in utero + postnatal) as well as delay in offspring development was higher in this group.

IL-3 es incapaz de rescatar células scid dependientes de IL-3 tras su exposición a irradiación por rayos X / IL-3 is unable to rescue IL-3-dependent scid cells after exposure to X-ray irradiation

Los factores de crecimiento pueden rescatar de la apoptosis a las células tras sufrir daños en su DNA, al regular diferentes mecanismos de reparación del DNA. En este trabajo hemos investigado el efecto radio-protector de la IL-3 en procesos de reparación de roturas de doble cadena del DNA, utilizando modelos celulares de cultivos primarios o una línea celular establecida, la CIT.1, derivada de medula ósea de ratones con inmunodeficiencia severa combinada (scid). Los ratones scid carecen de linfocitos T y B maduros debido a una mutación de la subunidad catalítica de la proteína DNA-PK, directamente implicada en la reparación de las roturas de doble cadenas producidas durante la recombinación V(D)J. Nuestros datos demuestran que la IL-3 es capaz de rescatar células Ba/F3, dependientes de este factor de proliferación, irradiadas con rayos X, pero no células de cultivos primarios o de la línea CIT.1, también dependientes de IL-3 y derivadas de ratones scid. La irradiación con rayos X reduce la actividad clonogénica de células derivadas de ratones scid, en contraposición con ratones normales, donde la IL-3 mantiene la clonogenicidad tras la irradiación. Sin embargo, utilizando bleomicina, droga radiomimética, la IL-3 fue capaz de rescatar tanto células derivadas de ratones normales como de ratones scid. La diferencia entra la capacidad de la IL-3 de rescatar células irradiadas o tratadas con bleomicina esta probablemente asociada a los diferentes mecanismos de inducción de daño utilizados por cada agente. Estos resultados implican a la DNA-PK en los procesos de radio-protección de la IL-3 tras irradiación y rotura de la doble cadena de DNA (AU)

Clinical evaluation of human placental extract (placentrex) in radiation-induced oral mucositis.

To evaluate human placental extract in the treatment of radiation mucositis involving the oral/oropharyngeal region, a prospective randomized study was carried out in 120 patients with squamous cell carcinoma of the head and neck from August 1997 to March 1999. The study was conducted in patients receiving radical external radiation therapy, planned for = > 60 Gy/30 F/6 weeks, who developed grade 2 radiation mucositis (patchy mucositis) during radiation treatment. The patients were randomized in two groups of 60 patients each to receive either placentrex treatment (placentrex group) or conventional treatment (control group). Placentrex treatment was given as Inj Placentrex 2 ml by deep intramuscular injection 5 days a week for 15 injections. Conventional treatment given in the control group was disprin gargles and betamethasone oral drops. A subjective decrease in pain was observed in 48/60 (80%) of patients in the placentrex group compared with 22/60 (36.7%) in the control group. The progression to grade 3 radiation mucositis was 24/60 (40%) in the placentrex group compared with 52/60 (86.7%) in the control group. The subjective improvement in difficulty in swallowing was seen in 56/60 (93%) of patients in the placentrex group compared with 9/60 (15%) of patients in the control group. Only one patient in the placentrex group compared with three in the control group required interruption of radiation therapy because of severe radiation reactions. Human placental extract appears to be effective in the management of radiation-induced oral/oropharyngeal mucositis and especially in controlling subjective symptoms.