Title: Human gammadelta T cells for immunotherapy of breast cancer
Funder: Tenovus Cancer Care

Abstract: Immunotherapy offers novel, safe and effective routes of treating cancer. Aminobisphosphonates (NBPs) are drugs that prevent bone resorption and are in clinical use for the treatment of tumour-associated bone disease. The ABCSG-12 trial demonstrated that adjuvant zoledronate reduces recurrence and enhances survival in patients receiving anti-hormones, with major implications for the management of early cancer. One possible mechanism stems from the activity of zoledronate on peripheral V9/V2T cells. By inhibition of the endogenous isoprenoid biosynthesis in target cells, NBPs lead to activation of these ‘unconventional’ lymphocytes, a class of human T cells with non-MHC-restricted anti-tumour activity. Our own recent clinical trials have highlighted a therapeutic benefit of T cells in metastatic breast and prostate cancer patients (Dieli et al., Cancer Research 2007; Meraviglia et al., Clinical and Experimental Immunology 2010), which we believe is mediated through selective tumour cell killing. This is clinically important as metastatic disease progression is the principal cause of death in breast cancer patients. Of note, V9/V2 T cells only exist in humans but not in laboratory animals. Thus, in order to test novel immunotherapy approaches for cancer patients both human cancer cells and human V9/V2 cells have to be transferred together into recipient animals, only then can their interaction be studied under conditions as they would exist in cancer patients This PhD project will explore the underlying mechanism of gammadelta T cell cytotoxicity in breast cancer, with the aim of increasing the therapeutic potential of gammadelta T cell based immunotherapy. The project will focus on the apoptosis inhibitor cFLIP, as preliminary data suggests that blocking this molecule not only increases the tumour cytotoxicity of gammadelta T cells but also sensitizes cancer stem cells to cell death. Using a mouse model of gammadelta T cell based immunotherapy in which both human cancer cells and human gammadelta T cells are co-transferred into recipient animals, this project aims to demonstrate in vivo that human gammadelta T cells can be pharmacologically activated to exert a cytotoxic effect on breast cancer cells and cancer stem cells, and that this effect can be enhanced by concomitant suppression of cFLIP. We propose to study the role of zoledronate-activated V9/V2 T cells in killing human breast cancer cells in vitro and in a SCID mouse model. We will study whether adoptively transferred V9/V2 T cells inhibit primary tumours and/or xenograft metastasis, and whether tumours can be sensitised by targeted knockdown of cFLIP. These complementary in vitro and in vivo studies will reveal the potential of V9/V2 T cells for immunotherapy of different types of breast cancer. Methods used will involve culture of breast cancer cell lines, RNAi-mediated knockdown, flow cytometry, real-time PCR, and immunofluorescence. Our study will help refine our current prescription of zoledronate in the clinic, by characterising beneficial effects on the patients’ immune system and by identifying potential responders.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS