ESTRO 37 Abstract book

S353

ESTRO 37

growth and metastasis of different cancer models. In accordance, genetic or pharmacological removal of chronic senescent cells delays cancer progression, but also improves overall healthspan. Together, our data suggest that despite cellular senescence playing an important tumor suppressive function, accumulation and persistence of senescent cells can paradoxically contribute to deleterious effects through cell-non- autonomous effects, including cancer promotion. The balance between positive and negative roles of cellular senescence needs to be taken into account for the generation of therapies aimed at interfering with the phenotype of senescent cells. SP-0677 Radiation, Senescence and salivary glands J. Axelrod 1 1 Hadassah Medical Center, Medical centre, Jerusalem, Israel Abstract text Radiotherapy treated head and neck cancer patients commonly suffer the devastating side-effect of dry-mouth syndrome (xerostomia), which results from the irreversible loss of salivary gland function via mechanisms that are not well understood. We will present evidence from experimental models in mice and from human patients that demonstrates a fundamental role of cellular senescence in the radiation-induced loss of salivary gland function. Radiation-induced senescence, evidenced by persistent DNA damage response, the expression of senescence associated markers and senescence associated secretory phenotype (SASP), including IL-6, without profound apoptosis or necrosis, closely accompanies salivary gland loss-of-function. Importantly, expression of IL-6 persists in the salivary gland long after initiation of radiation-induced DNA damage, and is crucial for both senescence and hypofunction. Similar senescence markers, including the presence of cytoplasmic chromosomal DNA, are observed in salivary glands excised from head and neck cancer patients treated with radiation. These findings indicate that cellular senescence is a fundamental mechanism driving radiation-induced salivary gland hypofunction and suggest novel strategies for its prevention. SP-0678 Stress induced senescence V. Gorgoulis 1 1 National Kapodistrian University of Athens, Histology- Embryology- Faculty of Medicine, Athens, Greece Abstract text 1. Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, 75 Mikras Asias Str, Athens, GR-11527, Greece. 2. Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Str, Athens, GR-11527, Greece. 3. Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester, M20 4QL, UK. Premature senescence, in contrast to Replicative senescence, is a telomere-independent stress response mechanism adopted by the cell to preserve its homeostasis. Radiation induced senescence belongs to a broader entity termed stress-induced premature senescence (SISP). Apart from irradiation, SISP can be induced by a variety of stressors including oncogenes (oncogene induced senescence), DNA damage (DNA damage induced senescence), oxidative stress (oxidative stress induced senescence) and others. Stress-induced senescent cells exhibit a plethora of features and activities that are largely independent of the stimulus and will be discussed. Within this line we will present: i)

an innovative biotinylated Sudan Black-B (SBB) analogue based hybrid histochemical/immunohistochemical assay (SenTraGor TM technology) that detects senescence in any biological material and ii) prototypical models of SISP to study genome and epigenome dynamics during senescence induction and senescence “escape”.

Symposium: Immunotherapy

SP-0679 Biological basis of radioimmunotherapy E. Deutsch 1 1 Institut Gustave Roussy, IDepartment of radiartion oncology- INSERM 1030, Villejuif, France Abstract text The immunosuppressive effects of radiation therapy have long been the only one considered. The predominant concept of a direct cell killing effect exerted on cancer cells directly, mostly though DNA damage repair and signaling processes has gained in complexity with the arousing of data underscoring the role of the tumor microenvironment into tumor’s response. Dying cancer cell may release signals which activate the surrounding immune cells, namely through the immunological cell death process. Irradiation can also increase the diversity of tumor neo antigens which are crucial to the induction of adaptive antitumor immunity. It has recently been shown that the inhibition of immune inhibitory checkpoints synergizes with ionizing radiation. Hypoxia is one of the key factors influencing clinical outcome after radiotherapy responsible for reduced local control that will influence overall survival, as may the hypoxic conditions by increasing malignant progression. The immune contexture of tumors might be correlated with outcome after irradiation. The purpose of tumor immunotherapy is based on the principle that reversal of tolerance to immunogenic tumors would be able to activate an immune response against tumor cells. The importance of the immune component into the process of tumor response to radiation offers novel opportunities for therapeutic interventions. Recently, novel insights regarding the pivotal role of the interferon response for both tumor local and abscopal response to radiotherapy provide a potential link between the DNA damage repair and signaling pathways and the induction of anti tumor immunity by radiotherapy. Preclinical data underscoring the potential of immune therapies as amplifiers of both the local and systemic anti tumor effect of radiotherapy do suggest the role of these agents for clinical transfert. However, manjor challenges remain such as optimizing the dose and fractionation, defining the best drug- irradiation scheduling and also the best type of immunological agent, the existence of a normal tissue versus tumor differential index. SP-0680 Toxicity profile of immune checkpoint inhibitors and combined radiotherapy treatment P.C. Lara Jimenez 1 1 Hospital Universitario de Gran Canaria Dr. Negrín, Academic Physics, Las Palmas de Gran Canaria- Ca, Spain Abstract text Immune chek point inhibitors (ICIs) are drugs that block the constitutive regulatory supressor mechanisms designed to prevent “autoinmune attacks” from the immune sytem, to normal tissue. These mechanisms are constitutive either in lymhocytes (CTL4/ PD-1/PD-L1) but also in tumour cells (PD-1/PDL-1). Therefore by “supressing the supressors” (using anti CTL4 , Anti PD-1 or anti PD-L1 antibodies) the immune system is free of the regulatory supressive signals and results reinvigorated to respond to antigen stimulii. Targeting these check-