117. Antitumor Immunity Induced by Adenovirus Vector-Mediated Transduction of OX40 Ligand

Abstract

As the field of Adenovirus (Ad) gene therapy continues to develop, alternate serotypes have been explored as a means to circumvent the disadvantages of Ad serotype 5 (Ad5)-based vectors. One such group of alternate serotypes that has been intensively investigated is the Ad subgroup B. Members of the Ad subgroup B have been found to efficiently transduce cells of the hematopoeitic system as well as more efficiently transduce malignant cells in a variety of neoplastic contexts compared to Ad5-based vectors. Whereas the majority of human Ad utilize the Coxsackie and Adenovirus Receptor (CAR) to infect cells, none of the Ad subgroup B utilize CAR. It has previously been demonstrated that Ad subgroup B, which are further divided into two groups: B1 and B2, utilize at least two distinct receptors. In this regard, CD46 has been implicated as the B2-specific receptor. Recently, Ad serotype 3 (Ad3), a member of Ad subgroup B1, was found able to utilize CD80 and CD86 as a primary cellular attachment receptors on human dendritic cells and the cervical carcinoma cell line HeLa. CD80 and CD86 are cell surface markers expressed on human dendritic cells and mature B-lymphocytes, and play a critical role in stimulating T-lymphocyte responses by their interaction with the ligands CD28 and CTLA-4. Both CD80 and CD86 are upregulated during the process of dendritic cell maturation and are often over-expressed in a variety of lymphocytic neoplasms and other neoplastic contexts. Whereas, CD80 and CD86 serve as the primary receptor for Ad3 on human dendritic cells, they play a more secondary role in HeLa infection. There exists a close homology between the knob domains of the Ad fiber, the receptor-interacting protein of the virion, of several members of subgroup B Ad. On this basis, we hypothesized that other members of the Ad subgroup B may utilize CD80 and CD86 as primary cellular attachment receptors. Recombinant knob domain of the Ad fiber from both B1 and B2 Ad could efficiently block CD80 and CD86-dependent infection of Ad3 vectors. All subgroup B members showed specific binding to cells expressing CD80 and CD86. Members of both B1 and B2 demonstrated CD80 and CD86-specific infection of CHO cells heterogenously expressing CD80 and CD86. Therefore, it appears that all of the members of Ad subgroup B can utilize CD80 and CD86 for infection of cells. Though these may not represent the only primary cellular receptors utilized by these viruses on all cells in the case of Ad3 they appear to play a critical role in the infection of human dendritic cells. This finding may help facilitate the construction of Ad subgroup B based vectors in the application of vaccine development and for vectors targeted towards CD80 and CD86 expressing neoplasms.