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A fiber-modified adenoviral vector interacts with immunoevasion molecules of the B7 family at the surface of murine leukemia cells derived from dormant tumors

Elodie Grellier1234, Katia Lécolle1234, Sophie Rogée1234, Cyril Couturier25, Jean-Claude D'Halluin13, Saw-See Hong6, Pascal Fender7, Pierre Boulanger6, Bruno Quesnel12348 and Morvane Colin1234*

Author Affiliations

1 INSERM UMR 837, 1, rue Polonovski, 59045 Lille, France

2 Univ. Lille Nord de France, 59000 Lille, France

3 Institut de Recherches sur le Cancer de Lille, Place de Verdun, 59045 Lille, France

4 Univ. Lille Nord de France, UDSL, Faculté de Médecine, IMPRT, JPARC, Place de Verdun, 59045 Lille, France

5 INSERM UMR 761, Biostructures & Drug Discovery, Université de Lille 2, Institut Pasteur de Lille, Faculté de Pharmacie de Lille, 3, rue du Professeur Laguesse. Institut Pasteur de Lille, IFR 142 - PRIM, 59000 Lille, France

6 Université Lyon 1 & UMR INRA-754, Rétrovirus & Pathologie Comparée, 50, avenue Tony Garnier, 69366 Lyon Cedex 07, France

7 Unit of Virus Host Cell Interactions (UVHCI), UMI 3265 (CNRS/UJF/EMBL), 6, rue Jules Horowitz, 38042 Grenoble, France

8 Service des Maladies du Sang, Centre Hospitalier et Universitaire de Lille, Rue Polonovski, 59000 Lille, France

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Molecular Cancer 2011, 10:105  doi:10.1186/1476-4598-10-105

Published: 31 August 2011


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.

B7-H1; B7.1; dormant leukemia cells; adenovirus; adenovirus vector; atadenovirus; chimeric fiber