Determination of the optimal stereotactic radiosurgery technique in the mouse brain metastasis model and investigation of its immunological effects

In brain metastases, which is still the most important cause of morbidity and mortality in cancer patients, local tumor control rates decrease due to the immunosuppressive properties of tumor cells and their resistance mechanisms. It is now known that stereotactic radiosurgery is effective for brain metastases and primary brain tumors, in regulating the immune response and tumor microenvironment, but there is not enough information on the effect of hypofractionated radiosurgery on the immune system in brain metastases. In addition, studies investigating the relationship of heat shock proteins and Hippo pathway, which have proven roles in the formation of resistance to treatment in different cancer types, with radiation in brain metastases, and the effects of different radiosurgical doses and fractions on these molecules are limited. For this purpose, we created a brain metastasis model in C57BL/6J mice with the B16F10 murine melanoma cell line. We divided mice into four groups; control and to be treated with Gamma Knife at different doses and fractions (15Gy, 3x7Gy, 5x5Gy). We measured survival times in each group. After separating healthy and tumor tissues from postmortem sacrified brain, we measured HSP90 and YAP1 levels from tumor tissues to evaluate their relationship with radiation resistance and the effect of different radiosurgical treatment schemes on these molecules by immunohistochemistry. We analyzed CCL4 and IL-17A levels to assess the immune response in tumor and healthy brain tissues by ELISA. We compared all collected data statistically. We found a significant difference in survival between the groups that received the treatment and the control group, the highest in the group that received 15 Gy Gamma Knife treatment. We did not detect a statistically significant difference in immunohistochemical analysis, between groups for HSP90 and YAP1 levels; with ELISA, between groups for CCL4 and IL-17A levels, and between healthy brain tissue and tumor tissue in each group. Although the effectiveness of stereotactic radiosurgery on immune response has been proven, effective and reliable doses and fractions of radiosurgery need to be determined, especially in order to overcome the radiation resistance mechanisms in brain metastases. In this context, we hope that our study will guide further studies. Keywords: gamma knife radiosurgery, HSP90, YAP1, radioresistance, immune response