Umor microenvironment. B7-H1 is constitutively expressed by several human tumors
Umor microenvironment. B7-H1 is constitutively expressed by several human tumors, and is induced when cancer cells are stimulated with interferon-gIFN-g) and ligands of Toll-like receptors (TLR) [7-9]. Using a DA1-3b mouse model of tumor dormancy, we previously demonstrated that a minor population of dormant leukemia cells persists in equilibrium with the immune system for long periods of time. Dormant leukemia cells suppressed CTL-mediated killing by overexpressing B7-H1 and B7.1 [10-12]. All these observations suggested that the B7-H1 and B7.1 molecules of the B7family could represent potential targets for new antitumor strategies (reviewed in [13]). Cell surface molecules in cancer cells have been considered as privileged targets in cancer therapy, but mostly as targets of therapeutic monoclonal antibodies (mAb) [14]. Alternative therapeutic methods include the use of oncolytic viral vectors naturally directed, or genetically retargeted to specific molecules of the cell surface, capable of triggering tumor cell death. Recombinant oncolytic adenoviruses offer several advantages over other oncolytic viral vectors: (i) they have a large cloning capacity, (ii) are relatively easy to produce to high titers, with vector stocks remaining stable over a long period of H 4065 biological activity storage, and (iii) their therapeutic effects do not require the viral DNA insertion into the host genome [15-18]. However, with the exception of certain members of species B adenoviruses, e.g. HAdV3, which have the natural ability to bind to B7.1 and B7.2 [19] and to efficiently transduce B7.1- and B7.2-expressing malignant glioma cells [20], the usage of adenoviruses in cancer gene therapy is limited, due to the low level (or absence) of expression of high affinity receptor for adenoviruses in cancer cells, or/and their poor accessibility at the cell surface. This is the case for the Coxsackie and Adenovirus human Receptor (hCAR), one of the natural receptors for adenoviral species A, C, D, E and F, which is located in the tight junctions and expressed at low levels in cancer cells [21], and for desmoglein-2, the receptor of HAdV3, also found in tight junctions [22]. Different strategies of adenoviral vectors have been proposed, and the most popular consisted of fiber capsomere modifications, to allow the vectors to attach to newly defined cell targets for efficient virus entry [15,17,18]. A fiber-modified, ?galactosidase (?gal)-expressing adenoviral vector, originally called HAdV5-F2/BAdV4 al and abbreviated Ad5FB4 in the present study, was previously constructed and characterized. Ad5FB4 is a human adenovirus serotype 5 which carries chimeric, human/bovine fibers [23-27]. It does not recognize the ubiquitous hCAR, and binds to cells via an attachmentreceptor different from the heparan sulfate proteoglycans [25]. Transduction of hCAR-negative and hCARpositive cells occurs via a clathrin-independent endocytic pathway involving lipid raft/caveolae [27]. An advantage of the altered tropism of the Ad5FB4 vector is the restriction of its infection repertoire of cells, which therefore limits the vector dissemination [24]. This results in the reduction of adenovirus-associated humoral and innate cytokine immune responses upon intravenous administration of Ad5FB4 vector to mice [26]. In the present study, we tested Ad5FB4 on malignant cells refractory to conventional Ad5-based vectors, and found that the permissiveness of murine leukemia cells to Ad5FB4 correlated with PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28300835 their dormancy.