Low dose radiotherapy promotes immune-mediated anti-tumor responses

Abstract

Abstract In an immune competent host, immune surveillance maintains the guards against abnormal cell growth, therefore establishing the need for tumors to evade immunity to grow. Tumors tend to mask themselves with an inhibitory stroma, rich with T regulatory cells, Myeloid-derived suppressor cells, Cancer associated fibroblasts, and pro-tumor M2 macrophages. Despite current advances with checkpoint inhibitors and cell-based therapies, the majority of cancer patients remain refractory to treatment due to the presence of the stroma and the inability of effector cells to penetrate. Radiotherapy (XRT) has been traditionally used to control tumors locally. More recently, we developed the RadScopal technique that combines high dose XRT (H-XRT) to release antigens and prime T-cells with low dose XRT (L-XRT) to overcome the stroma, favor the polarization of M1 macrophages, reduce TGF-β levels, and enhance NK cell infiltration. In the 129Sv/Ev murine model of bilaterally transplanted tumors, RadScopal treatment significantly improved the outcomes of anti-CTLA-4 and anti-PD1 checkpoint inhibitors and controlled the growth of primary as well as distal secondary tumors treated with L-XRT. The RadScopal efficacy was nulled when using nude mice lacking effector adaptive immunity. Moreover, specific immune-cell depletion studies highlighted the importance of CD4+ T-cells and NK cells to carry out the anti-tumor functions. Our radio-immunotherapeutic approach was operative in other models such as Lewis Lung Carcinoma, where L-XRT retarded the growth of secondary tumors. In conclusion, L-XRT significantly augmented checkpoint blockers with potential future application to cell therapies (CAR-T and TCR) to extend the benefits to more patients.