Inactivation of junctional adhesion molecule-A enhances antitumoral immune response by promoting dendritic cell and T lymphocyte infiltration.
Junctional adhesion molecule-A (JAM-A)-null dendritic cells (DCs) are more motile and effective than their wild-type counterpart in promoting contact hypersensitivity reaction. Here, we show that the growth and aggressiveness of pancreatic islet cell carcinoma induced by SV40 T antigen expression in beta cells (Rip1Tag2 mice) are significantly reduced in JAM-A-null mice. Because these tumor cells do not express JAM-A, we focused on changes in stroma reactivity. In the absence of JAM-A, tumors showed a small but significant reduction in angiogenesis and a marked increase in the immune reaction with enhanced infiltration of DCs (CD11c+ and MHC-II+) and CD4+ and CD8+ lymphocytes. In contrast, phagocyte number was not affected. DC capacity to produce cytokines was not significantly altered, but transmigration through JAM-A-null endothelial cells was increased as compared with JAM-A-positive endothelium. On adoptive transfer, JAM-A(-/-) DCs were recruited to tumors at slightly but significantly higher rate than JAM-A(+/+) DCs. Ablation of CD4+ and CD8+ cells with specific antibodies abrogated the inhibitory effect of JAM-A deletion on tumor growth and angiogenesis. These findings support the idea that, in the Rip1Tag2 tumor model, abrogation of JAM-A reduces cancer development by increasing antitumor immune response.
FIRC Institute of Molecular Oncology, Milan, Italy.
Masato
M
Murakami
Chiara
C
Francavilla
Ilaria
I
Torselli
Monica
M
Corada
Luigi
L
Maddaluno
Antonio
A
Sica
Gianluca
G
Matteoli
Iliyan Dimitrov
ID
Iliev
Alberto
A
Mantovani
Maria
M
Rescigno
Ugo
U
Cavallaro
Elisabetta
E
Dejana
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018273:Carcinoma, Islet Cell / Q000235:genetics / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics / Q000276:immunology
D015815:Cell Adhesion Molecules; C498686:F11r protein, mouse; D011956:Receptors, Cell Surface