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.

Immune-Mediated Effects of Microplanar Radiotherapy with a Small Animal Irradiator

“…Only the following two in vivo tumor models have been studied for comprehensive transcriptomic analysis after MRT: EMT6.5, a mouse breast cancer model, and 9L rat orthotopic glioblastoma [ 16 , 18 ]. In a very recent review, Trappetti et al performed a comparative gene expression analysis between these two studies [ 41 ]. Interestingly enough, CXCL9 was one of two candidates for the unique gene signature of MRT.…”

Radiobiological and Treatment-Related Aspects of Spatially Fractionated Radiotherapy

“…Findings from several preclinical studies using various animal models reported that the highly heterogenous dose deposition achieved with SFRT is associated with a superior immunological response in tumour tissue [ 24 , 25 ]. Tumour cell ablation from areas of peak dose is thought to discharge tumour antigen material that enables dendritic priming of T-cells.…”

“…Overexpression of genes after MRT (including Ccl9 and the human leukocyte antigen gene complex (HLA) family members responsible for encoding the major histocompatibility complex (MHC) Class II. Ccl9 expression) is responsible for the CCL9 chemokine known to recruit immune cells to tumour sites and also found to have an immunological role in signalling antileukemic responses [ 25 , 29 ]. Importantly, these transcriptomic studies give evidence of different genetic pathways of response to radiation exposure, dependent on MRT or conventional broad beam irradiation, suggesting a possible biological mechanism behind the greater efficacy observed in tumour control with SFRT.…”

A matter of space: how the spatial heterogeneity in energy deposition determines the biological outcome of radiation exposure

“…Another compelling hypothesis for the efficacy of SFRT involves the immune system. Several studies demonstrated a role of the immune system in the tumour response towards SFRT treatments (Bouchet et al 2013 , Yang et al 2019 , Trappetti et al 2021 ). It is well known that radiation therapy possesses immune stimulating effects (Formenti and Demaria 2013 , Vatner et al 2014 ), but it usually does not suffice to disrupt the immune tolerance against the tumour.…”