Adenosine suppresses α₄β₇ 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 (α_Lβ₂) or VLA-5 (α₅β₁). However, antibodies against either lymphocyte α₄ or β₇ (but not β₁) 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 α₄β₇ 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 α₄β₇ was functionally blocked with anti-α₄ antibodies (i) prior to or (ii) during the adhesion assay or if (iii) α₄⁺ cells were depleted from the T lymphocyte population. The binding of T cells to fibronectin through α₄β₁ 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 α₄β₇.