1. ¹Department of Pharmacology, School of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
2. ²Scott & White Cancer Research Institute, 5701 S. Airport Road, Temple, Texas 76502, USA

Correspondence: A Thorburn, Department of Pharmacology, University of Colorado Denver, Mail Stop 8303, PO Box 6511, Aurora, CO 80045, USA. Tel: +303 724 3290; Fax: +303 724 3663; E-mail: Andrew.Thorburn@uchsc.edu

Received 22 February 2008; Revised 4 September 2008; Accepted 4 September 2008; Published online 10 October 2008.

Abstract

Macroautophagy (hereafter referred to as autophagy) can increase or decrease the amount of cell death in response to various stimuli. To test whether autophagy also controls the characteristics associated with dying cells, we studied tumor cell killing by epidermal growth factor receptor-targeted diphtheria toxin (DT-EGF). DT-EGF kills epithelial and glioblastoma tumor cells with similar efficiency but by different mechanisms that depend on whether the cells activate autophagy when treated with the drug. Dying cells in which autophagy is induced selectively release the immune modulator high-mobility group B1 (HMGB1) without causing lysis of the cell membrane and classical necrosis. Conversely, cells that are killed by DT-EGF where autophagy is blocked, activate caspases but retain HMGB1. These data suggest that it may be feasible to manipulate the immunogenicity of dying cells by increasing or decreasing autophagy.