Date of Award


Degree Type


Degree Name

Doctor of Philosophy


The innate ability of the immune system to prevent the onset of cancer involves an intricate network of defense known as the natural killer (NK) cell system. As reactive elements in tumour defense and essential components of adoptive immunotherapy, NK cells represent a relatively new field of study that holds immeasurable potential in our struggle against cancer. Although their anti-tumour potential has been realized, NK cells and many of their regulatory processes, remain a scientific challenge. In order to exploit this system to its fullest potential, the functional mechanisms of NK-mediated tumour cell recognition and destruction must be fully understood through continued investigations into NK immunobiology. An effective method of studying the functional mechanism of any biological system, is to alter specific properties of that system and compare how the resultant changes affect the control system. Such a method of analysis has been adapted to the NK/target cell system using specialized applications of electron microscopy, flow cytometry and protein biochemistry. The incorporation of the phorbol ester and known tumour promoter, TPA, into our study has provided an ideal model for investigating the biochemical balance of intracellular events, such as proliferation, differentiation and the expression of surface molecules which affect the susceptibility level of tumour cells to NK-mediated cytolysis. By monitoring the pleiotropic responses of four leukemia/lymphoma cell lines to phorbol ester exposure, we have characterized the heterogeneity of tumour cell susceptibility to NK-mediated cytolysis.;The relationship of a proposed NK target molecule, the TfR, has been studied in various experimental models of NK/target interaction. Through an adapted technique of immuno-electron microscopy, combined with flow cytometric analysis, it has become evident that the expression of TfRs alone does not determine target sensitivity, but it is probable that TfRs are co-expressed and associated with the putative NK target molecule.;In an attempt to isolate a novel and yet, undefined molecule with reactivity within the NK/target cell system, we have examined an extensive protocol for the isolation of reactive fractions from tumour cell membranes. An automated two-parameter assay has been adapted specifically to the NK system to monitor conjugate formation within a mixed population as an indication of the reactivity of isolated fractions.;Combined with the ongoing efforts of other investigators, our theoretical and technical contributions to the field of NK immunobiology help to advance our knowledge of natural killer cells. Due to its potential in tumour defense, the NK system merits high priority in the field of cancer therapy and with continued research, we may eventually achieve success in its exploitation.



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