Combination of direct intratumoral administration of dendritic cells and irradiation induces strong systemic antitumor effect mediated by GRP94/gp96 against squamous cell carcinoma in mice.

We tested a new therapeutic modality for head and neck and esophageal cancers, a combination of direct intratumoral (i.t.) administration of dendritic cells (DCs) and radiation therapy (RT) in mouse squamous cell carcinoma (SCC). We also evaluated the functions of gp96, which can enhance systemic antitumor activity, and the mechanism of the abscopal effect. Mouse SCC cells (1 x 10(5)), SCCVII, were inoculated into the left femur of C3H/He mice subcutaneously, and also similarly inoculated into chest subcutaneous tissue. Only the left femur tumor was exposed to 4 or 10 Gy of ionizing radiation, and then 1 x 10(6) DCs i.t. was injected only into the femur tumor. Following this procedure, tumor volumes of the femur and chest were measured. We evaluated whether gp96 could enhance the antitumor effect. With DCs i.t. and RT, tumor growth was markedly suppressed. Tumor growth of non-treated tumors were also suppressed, indicating that the combination therapy of DCs and RT evoked systemic antitumor activity. In vitro, the enhancement of gp96 expression was strongly detected by immunostaining after irradiation, DCs with gp96 induced strong cytotoxic activity in vitro, and tumor growth inhibition was observed by direct i.t. injection of gp96. A combination of DCs i.t. and RT can induce a strong antitumor effect not only against treated local tumor but also against non-treated distant tumor, indicating that this treatment can evoke a strong systemic antitumor effect. Gp96 is thought to be one of the target molecules to explain the abscopal effect.