Modulation of T Lymphocytes by Tumor-Released Survivin

<p>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 tumor-secreted Survivin could be responsible for modulation of T lymphocytes in the tumor microenvironment. We first isolated tumor released Survivin and confirmed it’s 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 Survivin’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 and changes in regulatory T cells or Th17 cells in the presence of Survivin. The results of this study provide evidence of Survivin’s role as an extracellular mediator of the tumor microenvironment, specifically its role in inducing a pro-tumor type 2 T cell population.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Basic Sciences

Year

2014

Author dc:creator

• Jutzy, Jessica Marie

Contributors dc:contributor

• Wall, Nathan R.
• Duerksen-Hughes, Penelope
• Langridge, William
• Oberg, Kerby
• Payne, Kimberly

• Biochemistry
• Medical Biochemistry
• Medicine and Health Sciences
• Lymphocytes - Tumor-Infiltrating; T-Lymphocytes; Receptors - Antigen - T-cell; Cell Line - Tumor; Cell Migration Inhibition; Inhibitor of Apoptosis Proteins; Cytokines
• Survivin; Tumor Microenvironment; Extracellular Milieu; Phenotypic Changes

Statement dc:rights

• This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/243

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-1227