125I seed combined with DCS loaded with tumor antigen to convert irradiated liver cancer into effective in situ vaccine.

Abstract

e14573 Background: With unique feature of self-immune tolerance and high radio-sensitivity, hepatocellular carcinoma (HCC) can gradually develop undesired effects. Iodine-125 (125I) seed, as a source of internal radiation therapy, may have a favorable adaptability and immunostimulation. In this study, we investigated whether 125I seeds can stimulate local tumor infiltrating lymphocytes (TILs) and whether a combination of 125I seeds and dendritic cells (DCs) loaded with tumor antigen (Ag+DCs) can enhance both local tumor control and abscopal effect in murine subcutaneous tumor models. The related mechanism of anti-tumor immune response was also explored. Methods: H22/Hepa1-6 HCC cells were examined for radiosensitivity and immunosensitivity. Cell apoptosis and expression of MHC-I (major histocompatibility complex class I) and PD-L1 (programmed death-ligand 1) were detected before and after irradiation. The tumor cells were injected subcutaneously as primary and abscopal tumor. Bone marrow-derived dendritic cells (BM-DCs) were induced from mouse bone marrow cells and incubated with tumor cell lysate. 125I seeds were implanted into the primary tumors, followed by intratumoral injection of Ag+DCs and intraperitoneal injection of αPD1 antibody (αPD1-ab). DC migration was detected by transwell chambers in vitro and CFSE (carboxyfluorescein succinimidyl ester)-labeled DCs in vivo. DC maturation was tested by flow cytometry. Analyses of tumor growth and survival rates were performed in vitro, and that of, TILs, T-cell proliferation, cytotoxicity test, immunostimulatory cytokines release, and immunological memory were performed in vivo. In situ vaccine and abscopal effect were verified in orthotopic mouse models of liver cancer and lung metastatic tumor. Results: 125I seeds alone could induce TILs and activate cytotoxic T cells (CTLs), but these effects were limited. The combination treatment of 125I seeds with Ag+DC administration inhibited primary tumor growth and significantly prolonged survival time in association with a significant increase in T-cell proliferation and interferon-γ release. In addition, triple-combination treatment with αPD1-ab amplified these responses, leading to significant regression of primary and metastatic tumors and successful stimulation of immunological memory. Conclusions: 125I seeds can safely activate anti-tumor immune response.125I seeds combined with Ag+DC administration is able to convert irradiated liver cancer into effective in situ vaccine. Furthermore, triple-combination therapy of 125I seeds, Ag+DC, and αPD1-ab can be a promising approach to activate systemic anti-tumor immunity, which is a potential novel individualized therapy for patients with solid cancers.