Trappetti, Verdiana; Potez, Marine; Fernandez-Palomo, Cristian; Volarevic, Vladislav; Shintani, Nahoko; Pellicioli, Paolo; Ernst, Alexander; Haberthür, David; Fazzari, Jennifer M; Krisch, Michael; Laissue, Jean A; Anderson, Robin L; Martin, Olga A; Djonov, Valentin G (2022). Microbeam Radiation Therapy controls local growth of radioresistant melanoma and treats out-of-field locoregional metastasis. International journal of radiation oncology, biology, physics, 114(3), pp. 478-493. Elsevier 10.1016/j.ijrobp.2022.06.090
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1-s2.0-S0360301622007052-main.pdf - Accepted Version Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND). Download (2MB) | Preview |
PURPOSE
Synchrotron-generated microbeam radiotherapy (MRT) represents an innovative preclinical type of cancer radiotherapy with an excellent therapeutic ratio. Beyond local control, metastatic spread is another important endpoint to assess the effectiveness of radiotherapy treatment. Currently, no data exists on an association between MRT and metastasis. Here, we evaluated the ability of MRT to delay B16F10 murine melanoma progression and locoregional metastatic spread.
METHODS AND MATERIALS
We assessed the primary tumor response and the extent of metastasis in sentinel lymph nodes in two cohorts of C57BL/6J mice, one receiving a single MRT and another receiving two MRT delivered with a 10-day interval. We compared these two cohorts with synchrotron broad beam-irradiated and non-irradiated mice. In addition, using multi-plex quantitative platforms, we measured plasma concentrations of 34 pro- and anti-inflammatory cytokines and frequencies of immune cell subsets infiltrating primary tumors that received either one or two MRT treatments.
RESULTS
Two MRT treatments were significantly more effective for local control than single MRT. Remarkably, the second MRT also triggered a pronounced regression of out-of-radiation field locoregional metastasis. Augmentation of CXCL5, CXCL12 and CCL22 levels after the second MRT indicated that inhibition of melanoma progression could be associated with increased activity of anti-tumor neutrophils and T-cells. Indeed, we demonstrated elevated infiltration of neutrophils and activated T-cells in the tumors following the second MRT.
CONCLUSIONS
Our study highlights the importance of monitoring metastasis following MRT and provides the first MRT fractionation schedule that promotes local and locoregional control with the potential to manage distant metastasis.
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