Brachytherapy in a Single Dose of 10Gy as an “in situ” Vaccination

Abstract

<jats:p>Radiotherapy (RT) is one of the major methods of cancer treatment. RT destroys cancer cells, but also affects the tumor microenvironment (TME). The delicate balance between immunomodulation processes in TME is dependent, among other things, on a specific radiation dose. Despite many studies, the optimal dose has not been clearly determined. Here, we demonstrate that brachytherapy (contact radiotherapy) inhibits melanoma tumor growth in a dose-dependent manner. Doses of 10Gy and 15Gy cause the most effective tumor growth inhibition compared to the control group. Brachytherapy, at a single dose of ≥ 5Gy, resulted in reduced tumor blood vessel density. Only a dose of 10Gy had the greatest impact on changes in the levels of tumor-infiltrating immune cells. It most effectively reduced the accumulation of protumorogenic M2 tumor-associated macrophages and increased the infiltration of cytotoxic CD8+ T lymphocytes. To summarize, more knowledge about the effects of irradiation doses in anticancer therapy is needed. It may help in the optimization of RT treatment. Our results indicate that a single dose of 10Gy leads to the development of a robust immune response. It seems that it is able to convert a tumor microenvironment into an “in situ” vaccine and lead to a significant inhibition of tumor growth.</jats:p>

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“…However, the tumor microenvironment changes are primarily observed by the stimulation of the immune cells. Brachytherapy also increases the infiltration of cytotoxic CD8 + T lymphocytes and is responsible for reducing pro-tumorigenic M2 tumorassociated macrophages [32]. Brachytherapy also has an effect on tumor blood vessels.…”

“…Brachytherapy also has an effect on tumor blood vessels. Doses of more than 5 Gy reduce tumor blood vessel density [32]. In our experiments the dose of irradiation was chosen according to the literature, which indicates that radiotherapy in a dose of 2 Gy normalizes tumor blood vessels by reprograming the macrophages to the cytotoxic M1 phenotype [32,49,50].…”

“…Mice with well-developed tumors (60-80 mm 3 ) were anesthetized and treated with contact radiotherapy (brachytherapy), as described before [32]. Surface brachytherapy was performed with a dedicated, customized applicator (2 × 2 cm; Freiburg Flap, Elekta, Stockholm, Sweden) placed directly in the tumor area.…”

“…Radiotherapy destroys cancer cells, but also affects the tumor microenvironment, mainly by stimulation of immune cells. Cumulative doses of more than 5 Gy also reduce tumor blood vessel density [32]. Fuks et al showed that a single dose of more than 8-10 Gy and fractionated radiation of 1.8-3 Gy per fraction have strong antivascular effect [33].…”

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“…Target tumor-associated macrophages (TAMs). Brachytherapy in a single dose of 10 Gy can affect the TME by reducing the accumulation of pro-tumorigenic M2 polarized TAMs and by increasing CD8 + CTLs [ 174 ]. Low dose ionizing radiation (LDIR) programs macrophage differentiation to an inducible nitric oxide synthase (iNOS) positive M1 polarized phenotype that can orchestrate effective T cell immunotherapy, as demonstrated in a xenotransplant model of human pancreatic carcinoma [ 175 ].…”