Studies on IL-15 mediated anti-tumour immune responses in prostate cancer

• Main Author: Sakellariou, Christina Alexandra
• Other Authors: Smith, Richard ; Galustian, Christine ; Dasgupta, Prokar
• Published: King's College London (University of London) 2017
• Subjects: 616.99
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.718633

The prostate cancer (PCa) microenvironment is profoundly immunosuppressive and infiltrating immune cells (e.g. CD8 T cells, NK cells) become anergic or suppressive. Immunosuppression is thought to be a key factor in PCa progression and the site of the cancerous prostate is where the immune system is most compromised. We hypothesize that PCa can progress by tolerance to, and evasion of tumour cells from the immune system, and that therapies that act within the immunosuppressive PCa environment to reverse this immunosuppression are therefore desirable. A coculture system of human non-adherent peripheral blood mononuclear cells (PBMCs) and PCa cell lines was set up, where IL-15 was found to be the most potent activator of NK and NKT cells, inducing the expansion of these cells, and the NK- mediated killing of the PCa cells. Other therapeutic Th1 cytokines had no effect within this environment. Based on these results, the mechanisms of action of IL-15 on effector cell mediated killing of PCa cells in these coculture models were further investigated, by looking at its ability to modulate NK receptor and NK receptor ligand expression and interaction. It is shown that IL-15 enhances the NK cytotoxicity towards the PCa cells by upregulating the NKG2D receptor expression and downregulating both the surface and soluble expression of its ligand MICA. A key focus of this project was to create novel immunotherapeutic agents that can be localised in the prostate and to determine their efficacy. Having identified IL-15 as a cytokine that uniquely activates NK cells within PCa-effector cell cocultures, the technique of cytotopic tailing was used; this enabled the modification of recombinant human IL-15 and two antibodies to immune checkpoint inhibitors into a cytotopic form, whereby they can attach to the cell membrane and exert their functions more efficiently and for a prolonged period of time. The activity and function of tailed IL-15 and of the two tailed antibodies were tested in vitro as well as in an in vivo tumour challenge model of C57BL/6 mice injected with TRAMP-C2 tumour cells. Complete tumour clearance was observed in mice that were treated with the tailed cocktail of drugs, unlike the untailed version of this cocktail or the control.