Intratumoral expression of respiratory syncytial virus fusion protein in combination with cytokines encoded by adenoviral vectors as in situ tumor vaccine for colorectal cancer.

摘要

Although cancers can naturally elicit immune responses, immune ignorance is a common observation preventing immune-mediated elimination of tumor cells. We assessed whether intratumoral expression of respiratory syncytial virus fusion (RSV-F) protein, encoded by a replication-defective adenovirus vector (Ad.RSV-F), alone or in combination with local coexpression of cytokines can induce tumor-specific immune responses in a syngeneic murine colon cancer model. We confirmed in vitro by dye colocalization that transduction of murine cells with Ad.RSV-F induces cell-cell fusion. In vivo, we showed in a bilateral syngeneic s.c. colon cancer model in C57BL/6 and BALB/c mice that intratumoral injection of Ad.RSV-F leads to a significant volume reduction not only of the directly vector-treated tumor but also of the contralateral not directly vector-treated tumor. The intratumoral administration of Ad.RSV-F in combination with adenovirus vectors encoding interleukin (IL)-2, IL-12, IL-18, IL-21, or granulocyte macrophage colony-stimulating factor significantly enhanced the antitumor effect on the directly vector-treated tumor and also on the contralateral tumor. The antineoplastic efficacy of this combined treatment was significantly higher than that of the individual treatment components and was associated with the induction of a tumor-specific CTL response and increased infiltration of the tumors by natural killer cells and macrophages. Intratumoral coexpression of RSV-F and IL-21 resulted in the highest tumor growth inhibition and improved survival. Our experimental data indicate that intratumoral expression of RSV-F in combination with cytokines is a promising novel tool for the development of in situ tumor vaccination approaches.