Th balance related host genetic background affects the therapeutic effects of combining carbon-ion radiotherapy with dendritic cell immunotherapy

Abstract Purpose: The goal of this study is to clarify the underlying mechanisms of metastasis suppression by CiDC (carbon-ion radiotherapy (CIRT) combined with immature dendritic cell (iDC) immunotherapy), which was previously shown to significantly suppress pulmonary metastasis in a NR-S1-bearing C3H/He mouse model. Methods and Materials: Mouse carcinoma cell lines (LLC, LM8, Colon-26 and Colon-26MGS) were grafted into the right hind paw of syngeneic mice (C57BL/6J, C3H/He and BALB/c). Seven days later, the tumors on the mice were locally irradiated with carbon-ions (290 MeV/n, 6 cm SOBP, 1 or 2 Gy). At 1.5 days after irradiation, bone marrow-derived immature dendritic cells were administrated intravenously into a subset of the mice. The number of lung metastases was evaluated within three weeks after irradiation. In vitro cultured cancer cells were irradiated with carbon-ion (290 MeV/n, mono-energy, LET approximately 70 ∼ 80 keV/µm), and then co-cultured with iDCs for three days to determine the DC maturation. Results: CiDC effectively repressed distant lung metastases in cancer cell (LLC and LM8)-bearing C57BL/6J and C3H/He mouse models. However, Colon-26 and Colon-26MGS-bearing BALB/c models did not show enhancement of metastasis suppression by combination treatment. This was further evaluated by comparing LM8-bearing C3H/He and LLC-bearing C57BL/6J models with a Colon-26-bearing BALB/c model. In vitro co-culture assays demonstrated that all irradiated cell lines were able to activate C3H/He or C57BL/6J-derived iDCs into mature DCs, but not BALB/c-derived iDCs. Conclusion: The genetic background of the host may have a strong impact on the potency of combination therapy. Future animal and clinical testing should evaluate host genetic factors when evaluating treatment efficacy.