Related Experiment Videos
Soluble MUC1 secreted by human epithelial cancer cells mediates immune suppression by blocking T-cell activation
A K Chan1, D C Lockhart, W von Bernstorff
1Brigham and Women's Hospital, Harvard Medical School, Division of Surgical Oncology, Laboratory of Biologic Cancer Therapy, Boston, MA, USA.
Abstract:
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.
Insights
Tumor cell secretions can suppress immune responses. Soluble MUC1 from solid tumors inhibits T-lymphocyte proliferation and function by causing cell growth arrest.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Solid tumors can secrete immunosuppressive factors.
- Tumor-secreted factors impact immune cell function in cancer patients.
Purpose of the Study:
- To investigate the effect of human tumor cell line supernatants on T-lymphocytes.
- To identify the specific tumor-secreted molecules responsible for T-cell inhibition.
Main Methods:
- T-lymphocytes from healthy donors were cultured with tumor cell line supernatants.
- Fractionation of supernatants and molecular weight analysis were performed.
- Protein gel electrophoresis, Western blot, and immunoprecipitation were used to identify inhibitory molecules.
Main Results:
- Concentrated tumor supernatants inhibited T-lymphocyte proliferation, cytokine secretion, and cytotoxic activity.
- High molecular weight molecules (>100 kDa) in supernatants were responsible for inhibition.
- Soluble MUC1 was identified in inhibitory supernatants and its depletion reversed the inhibitory effects.
- Inhibited T-cells exhibited G(0)/G(1) phase cell cycle arrest and reduced immune marker expression.
Conclusions:
- MUC1 shed by cultured epithelial tumor cells mediates T-cell immune suppression.
- Soluble MUC1 induces T-cell growth arrest, inhibiting proliferation and function.
- Targeting soluble MUC1 may restore T-cell activity in cancer patients.