Radiation and Gold Nanoparticle Immunomodulation in MDA MB 231 Mouse Breast Cancer Model
Janic B, Neff R, Brown SL, Liu F, Mao G, Chetty IJ, Movsas B, and Wen N. Radiation and Gold Nanoparticle Immunomodulation in MDA MB 231 Mouse Breast Cancer Model. International Journal of Radiation Oncology Biology Physics 2020; 108(3):e545-e546.
International Journal of Radiation Oncology Biology Physics
Purpose/Objective(s): In recent years, radiation therapy (RT) has been evidenced to stimulate immune tumor rejection through immunomodulation of the tumor microenvironment (TME). One of the RT immunomodulation mechanisms include immunogenic cell death (ICD) that plays a major role in stimulating host anti-cancer immune response and can determine the success of cancer RT. The main feature of ICD is the release of immunogenic molecules by dying cells, termed damage associated molecular patterns (DAMPs) that act on innate and adaptive immune components to induce long-lasting antitumor immunity. Calreticulin (CRT) is a DAMPs molecule involved in phagocytosis and dendritic cell antigen presentation. In breast cancer (BC) calreticulin pronounced expression was associated with tumor metastatic potential and size. Therefore, DAMPs are being studied for their therapeutic and prognostic potential. As RT, either alone or in combination, is often part of standard BC therapies, the effect of RT and radiosensitizers (such as gold nanoparticles (AuNP)) on DAMPs expression must be considered when designing new protocols, especially if combining RT with an adjuvant mode such as immunotherapy. The goal of this study was to measure the effect of radiation on CRT expression and associated macrophage infiltration in the presence and absence of a novel AuNP radiosensitizer in MDA MB 231 BC mouse models. We hypothesize that AuNP modulates RT induced immunological changes such as increase in CRT expression and infiltration by F4/80 positive macrophages.
Materials/Methods: Female nude mice bearing MDA MB 231 tumors received intratumoral injections of 4nm or 14 nm AuNPs. After 24h mice were irradiated with 15 Gy dose using 160 kV photons. Mice were euthanized, histological sections prepared, stained with anti CRT and anti F4/80 antibodies and analyzed by light microscopy.
Results: In animals receiving RT or 14 nm AuNP only, CRT and F4/80 expression exhibited trend in increase relative to control but did not reach the significance. However, after the combined RT and AuNP (4nm or 14nm) treatment, CRT expression was further increased and reached the significance, compared to controls. However, F4/80 expression was significantly increased only in animals receiving the combination of RT and 14 nm AuNP, compared to controls (Table 1).
Conclusion: In BC patients, induction of ICD may play a critical role in improving clinical outcomes. Here we show that AuNP enhanced the immunogenic effect of a single RT dose in BC mouse model. This effect was measured by an increase in the expression of CRT and F4/80, an indicator of macrophage infiltration. These findings support the role of immunological mechanisms in BC depends and provide a platform for designing multimodal BC RT formulations with novel radiosensitizers or immunotherapy. [Formula presented]