Abstract 5947: Tumor cells escape cell death after radiotherapy by senescence - a mechanism that can be counteracted with zinc oxide nanoparticles

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Abstract Radiotherapy is still an important pillar for the therapy of head and neck squamous cell carcinoma (HNSCC); however, local recurrences arise in 15-50% of patients. During radiotherapy, there is a risk that individual tumor cells survive and proliferate again after a period of dormancy. Growing evidence suggests that senescence may play a key role in this context. We investigated in vitro radiotherapy-induced senescence and found that quiescent tumor cells survived treatment with 16 Gy. Those cells exhibited characteristics of senescence, yet were able to regain their proliferative capacity, and senescence was associated with radioresistance. During radiotherapy, the cells of the tumor stroma are inevitably irradiated as well. It is already known that cancer-associated fibroblasts (CAFs) can promote tumor progression. However, their contribution to the survival of senescent tumor cells after radiotherapy is unknown so far. Furthermore, the association between radiotherapy-induced senescence and recurrences raises the question of how residual, senescent tumor cells can be eliminated to prevent the development of a recurrence at an early stage. These aspects were the subject of the study presented here. To study the interaction between tumor cells and CAFs during their response to irradiation, both cell types were irradiated with 16 Gy in vitro individually and in co-culture. Subsequently, proliferation, cell death, morphological characteristics, and the secretome were analyzed. Additionally, we investigated whether senescent tumor cells can be targeted by treatment with zinc oxide nanoparticles. We could show that not only the tumor cells but also the CAFs go into a senescent state in response to irradiation, seen by loss of proliferation, increased senescence-associated β-galactosidase activity, and typical morphological characteristics. The secretome analysis revealed that the co-culture of tumor cells with CAFs significantly altered the repertoire of cytokines released upon irradiation, indicating intense communication between the cell types during their response to irradiation. Therefore, it is important for future studies on radiotherapy-induced senescence to include the tumor stroma as well. Finally, we demonstrated that senescent tumor cells were vulnerable to cell death induced by treatment with zinc oxide nanoparticles, which thus could potentially contribute to eliminating residual tumor cells after radiotherapy. This study revealed that radiotherapy-induced senescence in tumor cells and associated fibroblasts could well be a therapeutic problem, as senescent tumor cells are not targetable by radiotherapy anymore. In the future, zinc oxide nanoparticles may help to counteract this escape mechanism to prevent recurrences. Citation Format: Nadine Wiesmann, Rita Gieringer, Johannes Kupka, Jonas Eckrich, Sebahat Kaya, Peer Kaemmerer, Bilal Al-Nawas, Juergen Brieger. Tumor cells escape cell death after radiotherapy by senescence - a mechanism that can be counteracted with zinc oxide nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5947.