Rad, A; (2013) The Differential Influence of Allogeneic Tumour Cell Death via DNA Damage on Dendritic Cell Maturation and Antigen Presentation. Doctoral thesis , UCL (University College London).

Abstract

Dendritic cells (DC) respond to danger signals from tissue injury by amplifying their immune-inducing capacity. In the cancer context, this may lead to in vivo anti-tumour synergism between DC and DNA-damaging chemotherapeutic agents. Neither the interaction between DC and dying tumour cells, nor whether different ways of inducing cell injury can deliver danger signals of different strength to DC, has been studied rigorously. Furthermore, the physical interactions of DC with injured tumour cell, and whether physical contact is required for sensing danger signals, have not been clearly defined. Here we report that co-culture of immature DC with tumour cells treated with the alkylating agents Melphalan and Chlorambucil leads to enhanced autologous and allogeneic T-cell activation, up-regulation of surface expression of MHC and costimulatory molecules, and increased interleukin (IL)-12 secretion. However, exposure of DC to tumour cells killed by Cytarabine or by freeze-thaw (primary necrosis) resulted in significantly less T-cell proliferation and IL-12 production, indicating that DC are able to sense and respond differentially to the mode of cell death. Exposure of DC to DNA purified from tumour cells treated with alkylating agents also increased their T-cell-­stimulating capacity, expression of CD86, and IL-12 secretion, supporting the hypothesis that the activating effects of tumour cells are linked to the nature of the DNA damage. Furthermore, physical contact between DC and injured tumour cells is necessary for DC to sense and respond to danger signals. DC physically intereract with tumour cells via actin­and microtubule-dependent phagocytic mechanisms. This is the first study that shows that DC respond differentially to killed tumour cells, depending upon the mechanism of DNA damage and consequent T-cell death.

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