Date of Award

Fall 2012

Degree Type

Thesis

Degree Name

Master of Science (MSc)

Department

Medical Sciences (Molecular Virology and Immunology Program)

Supervisor

Ali Ashkar

Language

English

Committee Member

Dawn Bowdish, Jonathan Bramson

Abstract

NK cells play a pivotal role in tumor rejection; however, once present in the tumor microenvironment, they are characterized by decreased cytotoxicity and reduced expression of activating receptors. The mechanisms governing the inactivation of NK cells within tumors remain poorly understood. Since tumor associated macrophages (TAMs) are a highly abundant and suppressive cell type within tumors, we hypothesized that they are capable of altering the function of NK cells. Following the co-culture of alternatively activated macrophages (M2) or TAMs with NK cells we observed that the expression of the cytotoxic marker CD27 on NK cells was down-regulated as well as the ability of these cells to kill YAC-1 cells in a killing assay. We have demonstrated that the mechanism by which M2 cells inhibit NK cells is TGF-β dependent. Notably, the developmental stage of NK cells after interaction with TAMs was altered and the NK cells became phenoytpically mature and potentially exhausted (CD27lowCD11bhigh). This prompted our interest in examining the developmental stage of NK cells from polyoma MT antigen (pyMT) transgenic mouse (MMTV-pMT) breast tumors. Interestingly, in contrast to the in vitro results, we have shown that NK cells isolated from pyMT tumors are developmentally immature; however maintain their maturity within the spleen. Their immature phenotype correlates well with their decreased expression of perforin, granzyme, and NKp46. Both our in vitro studies with TAMs and our in vivo developmental studies using the pyMT model demonstrate that NK cells are altered by their surroundings. A better understanding of how NK cells are modified by the tumor microenvironment will help to develop strategies aimed at bolstering immune responses against tumors.

McMaster University Library

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