Immunogenic cell death

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death (apoptosis, autophagy or others) that do not elicit any response or even mediate immune tolerance.

The name 'immunogenic cell death' is also used for one specific type of regulated cell death that initiates an immune response after stress to endoplasmic reticulum.

Immunogenic cell death types are divided according to molecular mechanisms leading up to, during and following the death event. The immunogenicity of a specific cell death is determined by antigens and adjuvant released during the process.

Accidental cell death is the result of physical, chemical or mechanical damage to a cell, which exceeds its repair capacity. It is an uncontrollable process, leading to loss of membrane integrity. The result is the spilling of intracellular components, which may mediate an immune response.

ICD or immunogenic apoptosis is a form of cell death resulting in a regulated activation of the immune response. This cell death is characterized by apoptotic morphology, maintaining membrane integrity. Endoplasmic reticulum (ER) stress is generally recognised as a causative agent for ICD, with high production of reactive oxygen species (ROS). Two groups of ICD inducers are recognised. Type I inducers cause stress to the ER only as collateral damage, mainly targeting DNA or chromatin maintenance apparatus or membrane components. Type II inducers target the ER specifically. ICD is induced by some cytostatic agents such as anthracyclines, oxaliplatin and bortezomib, or radiotherapy and photodynamic therapy (PDT). Some viruses can be listed among biological causes of ICD. Just as immunogenic death of infected cells induces immune response to the infectious agent, immunogenic death of cancer cells can induce an effective antitumor immune response through activation of dendritic cells (DCs) and consequent activation of specific T cell response. This effect is used in antitumor therapy.

ICD is characterized by secretion of damage-associated molecular patterns (DAMPs).There are three most important DAMPs which are exposed to the cell surface during ICD. Calreticulin (CRT), one of the DAMP molecules which is normally in the lumen of the endoplasmic reticulum, is translocated after the induction of immunogenic death to the surface of dying cell. There it functions as an "eat me" signal for professional phagocytes. Other important surface exposed DAMPs are heat-shock proteins (HSPs), namely HSP70 and HSP90, which under stress condition also translocate to the plasma membrane. On the cell surface they have an immunostimulatory effect, based on their interaction with number of antigen-presenting cell (APC) surface receptors like CD91 and CD40 and also facilitate crosspresentation of antigens derived from tumour cells on MHC class I molecule, which then leads to the CD8+ T cell response. Other important DAMPs, characteristic for ICD are secreted HMGB1 and ATP. HMGB1 is considered to be a marker of late ICD and its release to the extracellular space seems to be required for the optimal presentation of antigens by dendritic cells. It binds to several pattern recognition receptors (PRRs) such as Toll-like receptors (TLR) 2 and 4, which are expressed on APCs. ATP released during immunogenic cell death functions as a "find-me" signal for phagocytes when secreted and induces their attraction to the site of ICD. Also, binding of ATP to purinergic receptors on target cells has immunostimulatory effect through inflammasome activation. DNA and RNA molecules released during ICD activate TLR3 and cGAS responses, both in the dying cell and in phagocytes.

The concept of using ICD in antitumor therapy has started taking shape with the identification of some inducers mentioned above, which have a potential as anti-tumor vaccination strategies. The use of ICD inducers alone or in combination with other anticancer therapies (targeted therapies, immunotherapies) has been effective in mouse models of cancer and is being tested in the clinic.

Another type of regulated cell death that induces an immune response is necroptosis. Necroptosis is characterized by necrotic morphology. This type of cell death is induced by extracellular and intracellular microtraumas detected by death or damage receptors. For example, FAS, TNFR1 and pattern recognition receptors may initiate necroptosis. These activation inducers converge on receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase domain like pseudokinase (MLKL). Sequential activation of these proteins leads to membrane permeabilization.