title: A fiber-modified adenoviral vector interacts with immunoevasion molecules of the B7 family at the surface of murine leukemia cells derived from dormant tumors.
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.
authors: INSERM UMR 837, 1, rue Polonovski, 59045 Lille, France.
authors: Elodie
authors: E
authors: Grellier
authors: Katia
authors: K
authors: Lécolle
authors: Sophie
authors: S
authors: Rogée
authors: Cyril
authors: C
authors: Couturier
authors: Jean-Claude
authors: JC
authors: D'Halluin
authors: Saw-See
authors: SS
authors: Hong
authors: Pascal
authors: P
authors: Fender
authors: Pierre
authors: P
authors: Boulanger
authors: Bruno
authors: B
authors: Quesnel
authors: Morvane
authors: M
authors: Colin
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism*; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D036022:Capsid Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007938:Leukemia; D051379:Mice; D011485:Protein Binding; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020349:Surface Plasmon Resonance; D019139:Tumor Escape; D017376:Viral Tail Proteins / Q000378:metabolism; D053585:Virus Attachment; D053586:Virus Internalization
chemical_list: D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D036022:Capsid Proteins; D011994:Recombinant Proteins; D017376:Viral Tail Proteins