Abstract
Micronuclei (MN) trigger antitumor immune responses via the cyclic GMP-AMP synthase-signaling effector stimulator of interferon genes (cGAS-STING) pathway. Radiotherapy induces MN in peripheral blood lymphocytes. However, data for solid tumors are lacking. Here, we analyzed MN post-radiotherapy in solid tumor samples. Tumor biopsy specimens were obtained from seven prospectively recruited patients with cervical cancer, before treatment and after receiving radiotherapy at a dose of 10 Gy (in five fractions). The samples were stained with 4′,6-diamidino-2-phenylindole dihydrochloride, and 200 nuclei per sample were randomly identified and assessed for the presence of MN or apoptosis, based on nuclear morphology. The median number of MN-harboring nuclei was significantly greater in samples from patients treated with radiotherapy than in pre-treatment samples (151 (range, 16–327) versus 28 (range, 0–61); p = 0.015). No significant differences in the number of apoptotic nuclei were observed between pre-treatment and 10 Gy samples (5 (range, 0–30) versus 12 (range, 2–30); p = 0.30). This is the first report to demonstrate MN induction by radiotherapy in solid tumors. The results provide clinical evidence of the activation of antitumor immune responses by radiotherapy.
Highlights
Immunotherapy is rapidly becoming a promising strategy for cancer treatment
At the present, identification of reliable biomarkers of response to cancer immunotherapy combined with radiotherapy represents one of the mainstream immune-oncology research lines [1]
Patients with cervical cancer were prospectively enrolled in the study if they met the following criteria: (a) pathologically-confirmed newly diagnosed cervical cancer; (b) treated with definitive RT at Gunma University Hospital between November 2017 and November 2018; (c) staged as IB1–IVA according to the 2009 International Federation of Gynecology and Obstetrics staging system; and (d) no previous exposure to radiotherapy or cytotoxic agents
Summary
Recent reports on the combination use of immunotherapy with radiotherapy (RT) are overwhelming [1,2] This kind of treatment strategy is hampered by the fact that its efficacy is unpredictable [1]. The cost for cancer immunotherapy is unsustainably high [1], a stratification of the patients who benefit from the combination treatment is needed. To this end, at the present, identification of reliable biomarkers of response to cancer immunotherapy combined with radiotherapy represents one of the mainstream immune-oncology research lines [1]. Micronuclei (MN) are induced following aberrant mitotic events in response to ionizing radiation, and are identified as one or a few smaller nuclei independent from the main nucleus [3,4]
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