Modulation of T Lymphocytes by Tumor-Released Survivin
The tumor microenvironment is an area of intense interaction between normal and malignant cells. Factors and cell types within this environment can play a crucial role in the progression or regression of the tumor. Of primary interest are tumor-infiltrating T lymphocytes, which have been shown to have a key role in modifying the dynamics of the tumor microenvironment to promote or prevent tumor growth. While there is much in vitro and in vivo evidence for a modification of the tumor infiltrating T cell population toward a pro-tumor environment, what induces these changes within the tumor microenvironment has remained elusive. Our lab previously identified a role for the Inhibitor of Apoptosis protein Survivin as a secreted protein in the extracellular milieu, where it is capable of entering malignant cells and inducing a more aggressive phenotype. We hypothesized that tumorsecreted Survivin could be responsible for modulation of T lymphocytes in the tumor microenvironment. We first isolated tumor released Survivin and confirmed its ability to be taken up by T cells as it is by malignant cells by confocal microscopy, flow cytometry and Western blotting. Subsequently, we evaluated Survivinâ€™s affect on T cell proliferation and found that tumor-released Survivin impairs T cell expansion, but does not alter its activation after exposure to appropriate stimuli. Assessment of phenotypic changes within the cytotoxic and helper T lymphocyte populations showed an increase in anti-inflammatory type 2 T cells and a reduction in type 1 T cells, which
correlates to what has been observed in cancer patients. Although often modified in the tumor microenvironment in patients, we did not observe any changes in regulatory T cells or Th17 cells in the presence of Survivin. The results of this study provide evidence of Survivinâ€™s role as an extracellular mediator of the tumor microenvironment, specifically its role in inducing a pro-tumor type 2 T cell population.
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