Guido Kroemer
Title:“Cell death in pathophysiology: inexorable, avoidable or desirable”
Apoptosis, Cancer and Immunity” Laboratory, University of Paris Descartes
Date:April 24, Thursday, 16.15
Location:Nobel Forum
Host: Boris Zhivotovsky
Contact:Tatiana Goriatcheva, Nobelkansliet, Nobel Forum, tel:+46-8-52487805, tatiana.goriatcheva@nobel.se
Abstract
Beyond the few potentially immortal gametes that our body produces, mortal (somatic) cells fall into two classes, those that are constantly renewed from proliferating stem cells, such as epithelial cells and leukocytes, and those that are not (or scarcely) renewed after birth, such as neurons or cardiomyocytes. While the former are programmed to undergo cell death and are replaced throughout life, the latter must endure until we expire. Excessive cell death, in particular in post-mitotic tissues, precipitates degenerative states, while the failure to timely execute death in renovating tissues contributes to hyperplasia and cancer. Our initial contribution to cell (death) biology consisted in the discovery that mitochondrial membrane permeabilization marks the inexorable point-of-no-return of lethal pathways, explaining why the inhibition of proteases and nucleases that contribute to cellular dismantling downstream of mitochondria cannot provide durable cytoprotection. We also demonstrated that autophagy is not a self-destructive pathway, as it had initially been thought, but rather a potent cytoprotective mechanism that, if induced on the whole-organism level, can increase the longevity of several animal species. Thus, autophagy contributes to the avoidance of the death of cells and organisms in the context of hormesis, the phenomenon whereby exposure to low, sublethal doses of an otherwise toxic agent subsequently increases resistance against damage and death. More recently, we invalidated the dogma that apoptosis, which is one particular modality of programmed or regulated cell death, is by definition a non-immunogenic cell death modality. We found that, depending on the upstream triggers and the premortem stress responses, apoptosis can be immunogenic and hence alert the innate immune system, instructing it to stimulate specific responses against dead-cell antigens. Several successful anticancer drugs that have saved millions of life-years induce this particularly ‘desirable’, immunogenic cell death type and hence convert cancers into a therapeutic vaccine that (re)activates tumor-specific immune responses. The induction of autophagy is one of the premortem events that favors the immunogenicity of apoptotic corpses.