Death, danger & immunity: Fundamental mechanisms linking pathogenic or iatrogenic cell death events to immune responses

This article introduces a series of reviews covering Death, Danger & Immunity appearing in Volume 280 of Immunological Reviews. The “natural,” non-accidental and non-violent death of human beings most often results from a protracted disease, the trajectory of which irremediably precipitates the progressive decline of vital functions until the point-of-no-returns is tragically trespassed. On a totally different scale, the death of individual cells within the human organism physiologically occurs in a close-to-imperceptible fashion because multiple homeostatic mechanisms assure the removal of corpses and their replacement by living cells, allowing the reconstitutio ad integrum, the complete restoration to original condition. Indeed, the mammalian organism is endowed with a sophisticated system that assures adequate recognition, removal and repair of dying and dead cells.1 This system is designed to avoid excessive inflammatory reactions that could cause local dysfunctions including scar formation and tissue fibrosis, as well as systemic disease. Moreover, physiological cell death usually does not cause any detrimental autoimmune response, meaning that immune tolerance usually is maintained upon exposure to dead-cell antigens.2 It is only when cell death occurs at a massive scale and when it is induced by non-physiological stimuli such as infectious pathogens, chemical agents, or irradiation that it results in inflammatory or immune reactions that have an impact on whole-body physiology.3, 4 The present issue of Immunological Review is dealing with the mechanistic links between Death, Danger and Immunity. Thus, major emphasis is laid on the danger signals that emanate from stressed and dying cells as danger-associated molecular patterns (DAMPs) or cell death-associated molecular patterns (CDAMPs) and that in fine determine whether cell death results in inflammatory and immune responses or not (Figure 1). Importantly, the cell death recognition system starts to come into action when cells are stressed, even before they die. This implies that it is not just the lethal event on its own that determines inflammatory and immune reactions against dead-cell antigens. Rather, the etiology of death, be it naturally “programmed,” accidental, infectious, or iatrogenic (ie induced by medical intervention), determines the outcome of local and system reactions, because each cause of death triggers a distinct spectrum of stress responses. Premortem stress can culminate in multiple changes in the cellular secretome that alert the microenvironment and potentially attract different leukocyte types toward the dying cells and then determine their activation and differentiation.5 The stress-associated secretome does not only include proteins but also metabolites including nucleotides and nucleosides.6 Importantly, premortem stress responses potentially affect gene expression patterns to increase the expression of ligands for receptors expressed on innate immune effectors such as NK cells.7 Moreover, premortem stress can cause the translocation of presynthesized intracellular proteins to the surface, thus providing “eat-me” signals to professional phagocytes. As a result, premortem stress determines the inflammatory and immunological tonus within tissues in which cell death occurs. When cells eventually succumb, it is important how they die, eg by apoptosis, necrosis, pyroptosis or other mechanisms, because each cell death subroutine entails a distinct pattern of cellular disintegration that has to be dealt with in a specific fashion by the tissue microenvironment. Obviously, the nature and functional state of phagocytes that have been recruited has a major impact on the way how corpses are handled.8 Phagocytes may rapidly scavenge cellular debris or, on the contrary, conserve portions of the engulfed dead-cell proteome to cross-present its antigenic peptides to T lymphocytes. This latter process is the privilege of dendritic cell precursors that require a panoply of differentiation and maturation signals to become effective cross-presenters. Obviously, the choice of the leukocytes attracted into the proximity of dying cells has a major influence on the inflammatory and immune consequences of the cell death event as well. Thus, one might conceive a sort of combinational code in which at least 4 elements come together to determine the immunological outcome of cell death: (i) the premortem stress signals with its associated DAMPs, (ii) the precise modality of cell death with its specific DAMPs, (iii) the recruited leukocyte populations and their response to DAMPs, and (iv) systemic pro- and inflammatory factors that may stimulate or dampen the local response.9 It appears plausible that the cascade of cellular and molecular events that links cell death to immunity has been designed by pathogen-host co-evolution in a way to guarantee for efficient responses to infection by cell death-inducing intracellular pathogens, in particular viruses.10 Indeed, there is ample evidence that each of the quintessential cell-autonomous responses to viral infection, including endoplasmic reticulum (ER) stress (to stall the production of viral proteins), autophagy (to destroy the infectious organism or its components), DNA damage responses (to cope with retroviral integration into the host genome), and interferon responses (to alert neighboring cells and to induce the expression of antiviral proteins), is tied to a cascade of intra- and extracellular signals that facilitates immune recognition of antigens encoded by the infectious pathogen. Obviously, human pathogens have elaborated a variety of strategies to suppress or elude these responses, namely, by suppressing ER stress and autophagy, by subverting DNA damage and interferon responses, and by inactivating essential nodes of pro-apoptotic or pro-necrotic signaling. Fortunately for us, these pathogenic strategies are imperfect, meaning that in most cases the immune system is able to abort acutely lethal or chronically smoldering infections. Immunogenic cell death (ICD), which almost certainly has evolved during the aforementioned host-pathogen co-evolution, plays a major role in anticancer therapies.11 Indeed, cancer cells are antigenically different from normal cells due to the expression of tumor-associated antigens, meaning that they can be recognized by T lymphocytes.12 Failing immunosurveillance appears to be one of the major bases of oncogenesis and tumor progression, implying that reinstating the immune recognition of malignant cells constitutes a major therapeutic goal. This view of cancer biology and therapy constitutes an authentic paradigm shift because it trespasses the previously cherished view that cancer is a purely cell-autonomous genetic and epigenetic disease, requiring eradication of the sick cells by molecules that target their intrinsic deviations. Intriguingly enough, several efficient chemotherapeutic agents that have been and are being successfully used for the treatment of malignancies possess the capacity to induce ICD. Thus, anthracyclines and oxaliplatin exemplify cytotoxicants that induce ICD while they stimulate the entire panoply of premortem stress responses that are usually induced by infectious pathogens and hence provide a sort of “viral mimicry.”13-15 As a possibility, clinical oncologist may have selected compounds and administration schedules that allow to kill cancer cells in a “noisy” fashion, as if they were infected by viruses to give rise to the release and exposure of all the DAMPs that are required for ICD. Indeed, there is accumulating evidence that the long-term success of close-to-all cancer therapies actually requires an anticancer immune response to be stimulated. Ironically, clinical oncologist may have been practicing immunotherapy without knowing, as they were administering cytotoxic chemotherapies or so-called targeted therapies. There is also accumulating evidence that successful radiotherapies induce ICD. ICD elicited by ionizing irradiation might explain why radiotherapy targeting one lesion may occasionally cause a systemic, presumably immune-mediated response leading to the control and even the disappearance of distant, untreated metastases. Obviously, it will be a challenge to administer radiotherapy in a way that it optimally triggers ICD, perhaps in the context of additional immunostimulatory measures that facilitate this “abscopal” effect.16-18 The aforementioned facts may explain why scientists that have previously been focusing on the development of cancer-specific cytostatic or cytotoxic drugs, as well as radiotherapists, all of a sudden have become profoundly interested in immunology. It is their collective hope that a profound comprehension of the danger signals that link cell death to therapeutically relevant immune responses will accelerate progress in the area. Given the huge economic incentive to generate immunotherapeutic antineoplastics, it would not be surprising that novel strategies for facilitating immune responses against infectious pathogens would be first developed by cancer researchers and then repurposed for the prevention and treatment of transmissible diseases. This work was supported by the Ligue contre le Cancer Comité de Charente-Maritime (équipe labelisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); Fondation Carrefour; the LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière: the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). The author declares no conflict of interest.