Microbeam Radiotherapy-A Novel Therapeutic Approach to Overcome Radioresistance and Enhance Anti-Tumour Response in Melanoma

Abstract

Melanoma is the deadliest type of skin cancer, due to its invasiveness and limited treatment efficacy. The main therapy for primary melanoma and solitary organ metastases is wide excision. Adjuvant therapy, such as chemotherapy and targeted therapies are mainly used for disseminated disease. Radiotherapy (RT) is a powerful treatment option used in more than 50% of cancer patients, however, conventional RT alone is unable to eradicate melanoma. Its general radioresistance is attributed to overexpression of repair genes in combination with cascades of biochemical repair mechanisms. A novel sophisticated technique based on synchrotron-generated, spatially fractionated RT, called Microbeam Radiation Therapy (MRT), has been shown to overcome these treatment limitations by allowing increased dose delivery. With MRT, a collimator subdivides the homogeneous radiation field into an array of co-planar, high-dose microbeams that are tens of micrometres wide and spaced a few hundred micrometres apart. Different preclinical models demonstrated that MRT has the potential to completely ablate tumours, or significantly improve tumour control while dramatically reducing normal tissue toxicity. Here, we discuss the role of conventional RT-induced immunity and the potential for MRT to enhance local and systemic anti-tumour immune responses. Comparative gene expression analysis from preclinical tumour models indicated a specific gene signature for an 'MRT-induced immune effect'. This focused review highlights the potential of MRT to overcome the inherent radioresistance of melanoma which could be further enhanced for future clinical use with combined treatment strategies, in particular, immunotherapy.

Keywords: immune response; melanoma; microbeam radiotherapy; oncology; radiotherapy; spatial fractionation; synchrotron.

Figure 1

Comparative gene expression analysis in MRT-irradiated tumours. (A) Table reporting the most important experimental parameters of the two compared studies (Sprung et al. [87] and Bouchet et al. [88]). ‘ref’ in (A) is reference [118]. (B) A Venn diagram displaying the common genes that are overexpressed after MRT in the two studies. For both studies, genes indicated as significantly modified were selected based on a fold-change ≥ 1.8 compared to un-irradiated controls. For the 9L glioblastoma (GB) study, gene expression was analyzed at 6 h post-irradiation (PI), while for the EMT6.5 mammary tumour study, three different time points were considered, 4, 24, and 48 h PI. These three different time points are reported as separate data sets in the diagram along with the single glioblastoma gene dataset. Common genes among the different groups are underlined in four different clusters, I to IV, and reported on the right side of the panel. In red are reported genes Ccl9 and Rsad2, which were significantly overexpressed in the comparison of MRT vs. BB analyzed in the EMT6.5 study. The VennPainter software was used to create the Venn diagram [109]. (C) The gene expression fold-change in tumours after MRT over the unirradiated control for two underlined genes Ccl9 and Rsad2. (D) The fold-change of the comparison MRT vs. BB from the study on EMT6.5 tumours for genes Ccl9 and Rsad2.

Figure 2

Schematic representation of the RT strategies for the treatment of melanoma. In the upper part of the figure, there is a schematic representation of melanoma irradiation with conventional RT (on the left) and MRT (on the right). In the lower part, the balance between positive and negative effects influencing treatment outcomes are represented (i.e., tumour control) for both RT modalities. On the left, we can see how the pro-tumour immune response, associated with radioresistance, outbalances the anti-tumour immune response induced by conventional RT. This leads to the current uncommon use of conventional RT for the treatment of melanoma. In the lower right panel, it is shown how the positive effects of MRT, such as induction of the anti-tumour immune response, overcoming melanoma radioresistance, and possible triggering of abscopal effects, shift the balance towards a better outcome for melanoma eradication. This promotes MRT as a new opportunity for melanoma treatment in future clinical settings.