Solid tumors may secrete factors that mediate immune suppression in patients. We investigated the effect of supernatants from 25 human tumor cell lines on T-lymphocytes from healthy donors. A profound inhibition of proliferation, cytokine secretion and cytotoxic activity was seen when T-cells were cultured in concentrated tumor supernatants from 6 cell lines fractionated into high (G100 kDa) m.w. molecules. Interestingly, the inhibitory effects were reversed when the tumor supernatant was removed. Cell cycle studies of inhibited T-cells showed most of them were growth arrested in the G 0 /G 1 phase similar to naΔ± Β¨ve T-cells. In addition, these T-cells did not express IL2-receptors and expression of CD54 (ICAM-1) and CD58 (LFA-3) resembled that of resting Tcells. Protein gel electrophoresis of the tumor supernatants and western blot analysis demonstrated the presence of soluble MUC1 in the inhibitory tumor supernatants but not in control supernatant. Most importantly, depletion of soluble MUC1 by immunoprecipitation from the tumor supernatants neutralized the inhibitory effects on T-lymphocytes. Therefore, our results show that MUC1 shed by cultured epithelial tumor cells mediates inhibition of T-cell proliferation and function by inducing cell growth arrest.