Anti-Tumor Immunity Induced by in Vivo Adenovirus Vector-Mediated Expression of CD40 Ligand in Tumor Cells

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Abstract
CD40 ligand (CD40L), the ligand for CD40 on antigen-presenting cells, is essential for the initiation of antigen-specific T cell responses, an important component of the immune response to tumors. This study is based on the hypothesis that in vivo genetic modification of tumor cells to express CD40L will trigger CD40 on local antigen-presenting cells to present tumor antigen to the cellular immune systems, thus eliciting anti-tumor immunity to suppress growth of the tumor. To examine this concept, subcutaneous tumors of three different murine tumor models in two strains of mice were infected with a recombinant adenovirus (Ad) vector expressing murine CD40L (AdmCD40L). In the B16 (H-2b, melanoma) and CT26 (H-2d, colon cancer) murine models, injection of AdmCD40L into established subcutaneous tumors resulted in sustained tumor regression and tumor-free status in >60% of animals. Intratumoral injection of AdmCD40L also significantly suppressed the growth of established, weakly immunogenic Lewis lung carcinoma (H-2b) tumors, but to a lesser extent. Ex vivo AdmCD40L-transduced tumor cells implanted in syngeneic hosts induced significant antitumor response against preexisting identical tumors at a distant site. Both in vivo and in vitro AdmCD40L modification of tumors to express CD40L elicited tumor-specific cytolytic T lymphocytes responses, and the transfer of spleen cells from treated mice efficiently protected naive mice against a subsequent tumor challenge. These results support the concept that transduction of tumors with a recombinant CD40L adenovirus vector may be a useful strategy for cancer immunotherapy.