The anti-tumour immune responses of γδ T cells activated with BCG, M. vaccae and M. obuense

• Main Author: Fowler, Daniel William
• Published: St George's, University of London 2011
• Subjects: 616.994079
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.559387

Introduction: BCG and heat-killed M. vaccae and M. obuense are currently being used as cancer immunotherapeutic agents; however, the induced immune response is poorly characterised and potential biomarkers of response ill-defined. γδ T cells have recently emerged as key players in immunity against both bacterial infections and malignant transformations, yet their role in cancer immunotherapies such as BCG, M. vaccae and M. obuense has been largely over-looked. This project investigates whether these three bacterial preparations can elicit anti-tumour responses in human peripheral blood γδ T cells. Methods: In this thesis, in vitro proof-of-concept experiments were conducted on human peripheral blood γδ T cells in order to test the activatory capacity of BCG, M. vaccae and M. obuense. To determine whether γδ T cells are activated by these bacterial preparations, activation marker expression and proliferation responses were assessed. Furthermore, the anti-tumour responses were also investigated by measuring cytokine production, expression of granzyme B and cytotoxicity against tumour target cells. In addition, the mechanism by which BCG, M. vaccae and M. obuense can activate these γδ T cell responses was assessed. Results: Results show that γδ T cells are activated by these three bacterial preparations, as suggested by upregulation of activation marker expression and proliferation responses. It was found that γδ T cells produce the T H1 cytokines IFN-y and TNF-a, and upregulate granzyme B expression, which correlates with an enhanced capacity to kill Daudi target cells and zoledronate-treated A549 cells. Results also suggest that γδ T cell responses are induced by IL-12, IL-1~ and TNF-a from a subpopulation of peripheral blood myeloid dendritic cells, and that M. obuense- but not BCG- or M. vaccae-induced cytokine production by these cells is, at least in part, dependent on TLR2 signalling. Conclusion: Taken together, data suggest a potential mechanism for the anti-cancer effects of BCG, M. vaccae and M. obuense, which could ultimately guide clinicians in harnessing the full potential of these bacterial preparations in cancer immunotherapy.