Abstract
Tumor cells can escape the immune system by overexpressing molecules of the B7 family, e.g. B7-H1 (PD-L1 or CD86), which suppresses the anti-tumor T-cell responses through binding to the PD-1 receptor, and similarly for B7.1 (CD80), through binding to CTLA-4. Moreover, direct interactions between B7-H1 and B7.1 molecules are also likely to participate in the immunoevasion mechanism. In this study, we used a mouse model of tumor dormancy, DA1-3b leukemia cells. We previously showed that a minor population of DA1-3b cells persists in equilibrium with the immune system for long periods of time, and that the levels of surface expression of B7-H1 and B7.1 molecules correlates with the dormancy time. We found that leukemia cells DA1-3b/d365 cells, which derived from long-term dormant tumors and overexpressed B7-H1 and B7.1 molecules, were highly permissive to Ad5FB4, a human adenovirus serotype 5 (Ad5) vector pseudotyped with chimeric human-bovine fibers. Both B7-H1 and B7.1 were required for Ad5FB4-cell binding and entry, since (i) siRNA silencing of one or the other B7 gene transcript resulted in a net decrease in the cell binding and Ad5FB4-mediated transduction of DA1-3b/d365; and (ii) plasmid-directed expression of B7.1 and B7-H1 proteins conferred to Ad5FB4-refractory human cells a full permissiveness to this vector. Binding data and flow cytometry analysis suggested that B7.1 and B7-H1 molecules played different roles in Ad5FB4-mediated transduction of DA1-3b/d365, with B7.1 involved in cell attachment of Ad5FB4, and B7-H1 in Ad5FB4 internalization. BRET analysis showed that B7.1 and B7-H1 formed heterodimeric complexes at the cell surface, and that Ad5FB4 penton, the viral capsomere carrying the fiber projection, could negatively interfere with the formation of B7.1/B7-H1 heterodimers, or modify their conformation. As interactors of B7-H1/B7.1 molecules, Ad5FB4 particles and/or their penton capsomeres represent potential therapeutic agents targeting cancer cells that had developed immunoevasion mechanisms.
Highlights
Tumor cells express numerous molecules at their surface that may influence their recognition by the immune system
In situ BRET analysis showed that B7.1 interacted with B7-H1 to form heterodimers at the cell surface, and that Ad5FB4 penton capsomeres interfered negatively with the formation of these complexes
We showed that leukemia cells DA1-3b/d365 derived from longterm dormant tumors, which are refractory to conventional adenovirus serotype 5 (Ad5)-based vectors, were permissive to Ad5FB4, an adenoviral vector carrying chimeric fibers
Summary
Tumor cells express numerous molecules at their surface that may influence their recognition by the immune system. Likely participates in T-cell exhaustion in cancer, as PD-1 is abundantly expressed on T-cells that infiltrate the tumor 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) [7,8,9]. Dormant leukemia cells suppressed CTL-mediated killing by overexpressing B7-H1 and B7.1 [10,11,12]. 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])
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