Adenosine suppresses alpha(4)beta(7) integrin-mediated adhesion of T lymphocytes to colon adenocarcinoma cells.
The interaction of T lymphocytes with tumor cells, a key step in the antitumor immune response, is suppressed by adenosine, a nucleoside produced at increased levels within the hypoxic tumor environment. We have explored the mechanism by which adenosine interferes with the lymphocyte:tumor cell interaction. The adhesion of anti-CD3-stimulated T cells to syngeneic MCA-38 mouse colon adenocarcinoma cells did not involve LFA-1 (alpha(L)beta(2)) or VLA-5 (alpha(5)beta(1)). However, antibodies against either lymphocyte alpha(4) or beta(7) (but not beta(1)) integrin subunits, or against VCAM-1 on the tumor cells, significantly suppressed adhesion, showing that the recognition of MCA-38 cells by T cells is strongly dependent upon the association of alpha(4)beta(7) on the effector cells with VCAM-1 on the tumor targets. This association is modulated by adenosine: The ability of adenosine to suppress T cell adhesion to MCA-38 cells was lost if alpha(4)beta(7) was functionally blocked with anti-alpha(4) antibodies (i) prior to or (ii) during the adhesion assay or if (iii) alpha(+)(4) cells were depleted from the T lymphocyte population. The binding of T cells to fibronectin through alpha(4)beta(1) was not suppressed by adenosine. We conclude that adenosine partially inhibits the interaction of T lymphocytes with tumor cells by blocking the function of integrin alpha(4)beta(7).
MacKenzie
Willena M
WM
Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.
Hoskin
David W
DW
Blay
Jonathan
J
D000230:Adenocarcinoma / Q000276:immunology*; D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000276:immunology*; D005353:Fibronectins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017469:Receptors, Fibronectin / Q000502:physiology; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D005353:Fibronectins; D007166:Immunosuppressive Agents; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D017469:Receptors, Fibronectin; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; C071777:integrin alpha4beta7; D000241:Adenosine