IL‐4 inhibits VLA‐4 expression on Tc1 cells resulting in poor tumor infiltration and reduced therapy benefit

Abstract

We and others have previously demonstrated that IL‐4‐dependent Tc2 are inferior to Tc1‐effector CD8⁺ T cells in regulating tumor progression in vivo. This functional disparity relates, in part, to the comparatively poor ability of Tc2 to migrate into diseased tissues. We now show that IL‐4 treatment of committed Tc1 cells promotes the selective loss in the expression of very‐late antigen (VLA)‐4, without impacting the Tc1 cytokine production profile, cytotoxic activity, or expression of alternate cell surface markers. Down‐regulation of VLA‐4 expression on Tc1 cells was unique to treatment with IL‐4 (i.e. Tc1^IL‐4) and did not occur in the presence of the Type‐2 cytokine IL‐13 or the regulatory cytokines IL‐10 or TGF‐β. Notably, the inhibitory effects of IL‐4 on Tc1 expression of VLA‐4 could be blocked by the presence of IL‐12, but not IFN‐γ. Predictably, Tc1^IL‐4 (but not Tc1 control) cells adhere poorly to plate‐bound VCAM‐1‐Fc fusion protein and fail to be co‐stimulated by VCAM‐1 in vitro. They were also markedly impaired in their ability to traffic into intracranial melanoma lesions after adoptive transfer, yielding inferior therapeutic benefit to tumor‐bearing mice. These results suggest a novel suppressive mechanism for IL‐4 that limits Tc1 efficacy via preventing their recruitment into tumors.