Administration of Dendritic Cells and Anti-PD-1 Antibody Converts X-ray Irradiated Tumors Into Effective In situ Vaccines

Abstract

Danger signals and release of tumor-specific antigens after exposure to ionizing radiation can convert an irradiated tumor into an in situ vaccine. However, radiation alone is not sufficient to induce an effective systemic immune response. In this study, we investigated whether a combination of x-ray irradiation with bone marrow-derived dendritic cells (BM-DCs) and anti-PD-1 antibody (αPD1-ab) administration can enhance both local tumor control and the systemic abscopal effect in murine subcutaneous tumor models. B16/BL6 melanoma and Lewis lung carcinoma cells were examined for radiosensitivity and expression of H-2kd and PD-L1 before and after irradiation. The tumor cells were implanted subcutaneously in the left thigh of C57BL/6 mice as primary tumors. BM-DCs were induced from mouse bone marrow cells using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The primary tumors were treated with 8Gy of x-ray, followed by simultaneous intratumoral injection of BM-DCs and intraperitoneal injection of αPD1-ab. To examine the abscopal effect, the same tumor cells were also inoculated in the right thigh as metastatic tumors 4days after the primary tumor inoculation, and only the primary tumors were treated with the same protocols. Invivo analyses of tumor growth and survival rates and in vitro analyses of splenic T-cell proliferation and interferon-γ release were performed. The triple-combination treatment of x-ray irradiation with BM-DC and αPD1-ab administration inhibited primary tumor growth and significantly extended survival time in association with significant increase of T-cell proliferation and interferon-γ release. In addition, this triple-combination treatment significantly inhibited the growth of metastatic tumors. The results indicated that BM-DC and αPD1-ab administration led to the conversion of irradiated tumors into effective in situ vaccines. This combination therapy can be a promising approach to develop a novel individualized therapy for patients with solid cancers.