Modulation of T Lymphocytes by Tumor-Released Survivin

Jessica Ms Jutzy,Nathan R Wall

doi:10.18314/gjct.v3i1.122

Abstract

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, whichcorrelates 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.

Highlights

Characteristics of Cancer CellsCancer is a complex disease involving the accelerated and uncontrolled proliferation of abnormal cells that invade normal tissues
While normal human cells have a replicative capacity of approximately 60-70 divisions, malignant cells frequently exceed this limit, providing enough cells to form a tumor despite death of many of the pre-malignant cells along the way [2,3]
The overall shift from a type 1 to a type 2 response was shown both by the decrease in IFN-γ+ T cells and the increase in IL-4+, IL-5+ and IL13+ T cells in response to Survivin. These findings demonstrate a role for Survivin in mediating the shift from a type 1 to a type 2 T cell response in the tumor microenvironment

Summary

Introduction

Cancer is a complex disease involving the accelerated and uncontrolled proliferation of abnormal cells that invade normal tissues. Through production of matrix metalloproteinases (MMPs) and decreasing cell-cell adhesion molecules like E-cadherin, cancer cells can move away from the tumor and past the basement membrane barrier to invade nearby tissues as well as metastasize to distant locations [9,10] This metastatic function is part of what makes treatment of cancer incredibly difficult, as simple surgical techniques cannot be used systemically to eradicate the malignancy. The type 1 or M1 phenotype is primarily proinflammatory and has an excellent capacity for killing cancer cells, presenting their antigens and activating an adaptive immune inflammatory response against the tumor [14]. These functions are mediated by the production of tumor necrosis factor alpha (TNF-α) and nitric oxide (NO). Increased amounts of VEGF can impair DC maturation and it is suspected that other cytokines produced in the tumor microenvironment play an additional role [14]

B Lymphocytes

Findings

Conclusion