Amplifying radiation-induced anti-tumor immunity: the dual role of brachytherapy and low-dose total body irradiation

Background: Radiotherapy can be a vaccine by triggering patients' prophylactic tumor-specific immune responses. Brachytherapy has biological and physical benefits over external beam radiation. Low-dose total body irradiation can produce systemic immunity. We hypothesized that brachytherapy more effectively modulates immunity than external beam radiotherapy, with low-dose total body irradiation amplifying this effect. Methods: After creating the Lewis lung cancer model, we compared hypo-fractionated brachytherapy with hypo-fractionated radiotherapy, examining immunogenic cell death, DNA damage, cell proliferation and immune cells in tumor. We then evaluated if low-dose whole-body irradiation could boost hypo-fractionated brachytherapy's systemic immunomodulatory effects and trigger a distant response. Results: Hypo-fractionated brachytherapy was more effective in inhibiting tumor growth than external beam radiotherapy. Hypo-fractionated brachytherapy approach significantly influenced various immune cells within the tumor microenvironment, including T cells, DC cells, NK cells, MDSC cells, tumor-associated macrophages. Furthermore, low-dose total body irradiation at 0.1 Gy augmented the immunological effects of low-fractionation brachytherapy and elicited transient systemic immune activation in mice. Conclusions: Our research indicates that brachytherapy offers superior immune modulation over external radiotherapy. When combined with low-dose total body irradiation, it transiently activates the systemic immune response.