Soluble MUC1 secreted by human epithelial cancer cells mediates immune suppression by blocking T-cell activation.
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 (>100 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 naïve 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 T-cells. 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.
Brigham and Women's Hospital, Harvard Medical School, Division of Surgical Oncology, Laboratory of Biologic Cancer Therapy, Boston, MA, USA.
A K
AK
Chan
D C
DC
Lockhart
W
W
von Bernstorff
R A
RA
Spanjaard
H G
HG
Joo
T J
TJ
Eberlein
P S
PS
Goedegebuure
D015153:Blotting, Western; D018968:CD58 Antigens / Q000096:biosynthesis; D002455:Cell Division; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008970:Molecular Weight; D018396:Mucin-1 / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D014407:Tumor Cells, Cultured
D018968:CD58 Antigens; D018396:Mucin-1; D015375:Receptors, Interleukin-2; D018799:Intercellular Adhesion Molecule-1