IL-4 inhibits VLA-4 expression on Tc1 cells resulting in poor tumor infiltration and reduced therapy benefit.
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. Tc1IL-4) and did not occur in the presence of the Type-2 cytokine IL-13 or the regulatory cytokines IL-10 or TGF-beta. 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-gamma. Predictably, Tc1IL-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.
Sasaki
Kotaro
K
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Pardee
Angela D
AD
Okada
Hideho
H
Storkus
Walter J
WJ
D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D007167:Immunotherapy; D039041:Integrin alpha4beta1 / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology* / Q000494:pharmacology; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism
D039041:Integrin alpha4beta1; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma