Microbeam Radiation Therapy Controls Local Growth of Radioresistant Melanoma and Treats Out-of-Field Locoregional Metastasis

Abstract

Synchrotron-generated microbeam radiation therapy (MRT) represents an innovative preclinical type of cancer radiation therapy with an excellent therapeutic ratio. Beyond local control, metastatic spread is another important endpoint to assess the effectiveness of radiation therapy treatment. Currently, no data exist on an association between MRT and metastasis. Here, we evaluated the ability of MRT to delay B16F10 murine melanoma progression and locoregional metastatic spread. We assessed the primary tumor response and the extent of metastasis in sentinel lymph nodes in 2 cohorts of C57BL/6J mice, one receiving a single MRT and another receiving 2 MRT treatments delivered with a 10-day interval. We compared these 2 cohorts with synchrotron broad beam-irradiated and nonirradiated mice. In addition, using multiplex 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 1 or 2 MRT treatments. Two MRT treatments were significantly more effective for local control than a 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 antitumor neutrophils and T-cells. Indeed, we demonstrated elevated infiltration of neutrophils and activated T-cells in the tumors after the second MRT. Our study highlights the importance of monitoring metastasis after MRT and provides the first MRT fractionation schedule that promotes local and locoregional control with the potential to manage distant metastasis.