Immunogenic cell death

Immunogenic cell death or immunogenic apoptosis is a form of cell death caused by some cytostatic agents such as anthracyclines,[1] oxaliplatin and bortezomib, or radiotherapy and photodynamic therapy (PDT).[2] Unlike normal apoptosis, which is mostly nonimmunogenic or even tolerogenic, immunogenic apoptosis of cancer cells can induce an effective antitumour immune response through activation of dendritic cells (DCs) and consequent activation of specific T cell response.[3] Most of the agents inducing immunogenic cell death are targeting endoplasmic reticulum (ER), leading to ER stress and production of reactive oxygen species (ROS). Both ER stress and ROS production are key players of intracellular signaling pathways that govern ICD.[4] 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 endoplasmic reticulum (ER), is translocated after the induction of immunogenic apoptosis to the surface of dying cell where 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 are under stress condition also translocated 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 than leads to the CD8+ T cell response. Other important DAMPs, characteristic for ICD are secreted amphoterin (HMGB1) and ATP.[5][6] HMGB1 is considered to be late apoptotic marker and its release to the extracellular space seems to be required for the optimal release and presentation of tumour antigens to dendritic cells. It binds to several pattern recognition receptors (PRRs) such as Toll-like receptor (TLR) 2 and 4, which are expressed on APCs. The most recently found DAMP released during immunogenic cell death is ATP, which functions as a "find-me" signal for monocytes when secreted and induces their attraction to the site of apoptosis.[7]

The concept of ICD has started taking shape over past few years, there were found some inducers mentioned above, which have a potential as anti-tumour vaccination strategies. The use of ICD inducers alone or in combination with other anticancer therapies (targeted therapies, immunotherapies [8]) has been effective in mouse models of cancer[9] and is being tested in the clinic.[10]


  1. ^ Obeid, Michel; Tesniere, Antoine; Ghiringhelli, François; Fimia, Gian Maria; Apetoh, Lionel; Perfettini, Jean-Luc; Castedo, Maria; Mignot, Grégoire; Panaretakis, Theoharis (2007-01-01). "Calreticulin exposure dictates the immunogenicity of cancer cell death". Nature Medicine. 13 (1): 54–61. doi:10.1038/nm1523. ISSN 1078-8956. PMID 17187072.
  2. ^ Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P (2010). "Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation". Biochim Biophys Acta. 1805 (1): 53–71. doi:10.1016/j.bbcan.2009.08.003. PMID 19720113.
  3. ^ Spisek R, Dhodapkar MV (2007). "Towards a better way to die with chemotherapy: role of heat shock protein exposure on dying tumor cells". Cell Cycle. 6 (16): 1962–5. doi:10.4161/cc.6.16.4601. PMID 17721082.
  4. ^ Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P (2012). "Immunogenic cell death and DAMPs in cancer therapy". Nat Rev Cancer. 12 (12): 860–75. doi:10.1038/nrc3380. PMID 23151605.
  5. ^ Apetoh, Lionel; Ghiringhelli, François; Tesniere, Antoine; Obeid, Michel; Ortiz, Carla; Criollo, Alfredo; Mignot, Grégoire; Maiuri, M. Chiara; Ullrich, Evelyn (2007-09-01). "Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy". Nature Medicine. 13 (9): 1050–1059. doi:10.1038/nm1622. ISSN 1078-8956. PMID 17704786.
  6. ^ Ghiringhelli, François; Apetoh, Lionel; Tesniere, Antoine; Aymeric, Laetitia; Ma, Yuting; Ortiz, Carla; Vermaelen, Karim; Panaretakis, Theocharis; Mignot, Grégoire (2009-10-01). "Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors". Nature Medicine. 15 (10): 1170–1178. doi:10.1038/nm.2028. ISSN 1546-170X. PMID 19767732.
  7. ^ Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, et al. (2012). "A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death". EMBO J. 31 (5): 1062–79. doi:10.1038/emboj.2011.497. PMC 3298003. PMID 22252128.
  8. ^ Pfirschke, Christina; Engblom, Camilla; Rickelt, Steffen; Cortez-Retamozo, Virna; Garris, Christopher; Pucci, Ferdinando; Yamazaki, Takahiro; Poirier-Colame, Vichnou; Newton, Andita; Redouane, Younes; Lin, Yi-Jang; Wojtkiewicz, Gregory; Iwamoto, Yoshiko; Mino-Kenudson, Mari; Huynh, Tiffany G.; Hynes, Richard O.; Freeman, Gordon J.; Kroemer, Guido; Zitvogel, Laurence; Weissleder, Ralph; Pittet, Mikael J. (February 2016). "Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy". Immunity. 44 (2): 343–354. doi:10.1016/j.immuni.2015.11.024.
  9. ^ Zitvogel, Laurence; Galluzzi, Lorenzo; Smyth, Mark J.; Kroemer, Guido (July 2013). "Mechanism of Action of Conventional and Targeted Anticancer Therapies: Reinstating Immunosurveillance". Immunity. 39 (1): 74–88. doi:10.1016/j.immuni.2013.06.014.
  10. ^ Garg, Abhishek D.; More, Sanket; Rufo, Nicole; Mece, Odeta; Sassano, Maria Livia; Agostinis, Patrizia; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo (4 October 2017). "Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics". OncoImmunology. 6 (12): e1386829. doi:10.1080/2162402X.2017.1386829.
Algor mortis

Algor mortis (Latin: algor—coldness; mortis—of death), the second stage of death, is the change in body temperature post mortem, until the ambient temperature is matched. This is generally a steady decline, although if the ambient temperature is above the body temperature (such as in a hot desert), the change in temperature will be positive, as the (relatively) cooler body acclimates to the warmer environment. External factors can have a significant influence.

The term was first used by Dowler in 1849. The first published measurements of the intervals of temperature after death were done by Dr John Davey in 1839.

Cell death

Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, or may result from such factors as disease, localized injury, or the death of the organism of which the cells are part. Apoptosis or Type I cell-death, and autophagy or Type II cell-death are both forms of programmed cell death, while necrosis is a non-physiological process that occurs as a result of infection or injury.

Dead on arrival

Dead on arrival (DOA), also dead in the field and brought in dead (BID), indicates that a patient was found to be already clinically dead upon the arrival of professional medical assistance, often in the form of first responders such as emergency medical technicians, paramedics, or police.

In some jurisdictions, first responders must consult verbally with a physician before officially pronouncing a patient deceased, but once cardiopulmonary resuscitation is initiated, it must be continued until a physician can pronounce the patient dead.

Death hoax

A death hoax is a deliberate or confused report of someone's death that turns out to be incorrect and murder rumors. In some cases it might be because the person has intentionally faked death.

Death messenger

Death messengers, in former times, were those who were dispatched to spread the news that an inhabitant of their city or village had died. They were to wear unadorned black and go door to door with the message, "You are asked to attend the funeral of the departed __________ at (time, date, and place)." This was all they were allowed to say, and were to move on to the next house immediately after uttering the announcement. This tradition persisted in some areas to as late as the mid-19th century.

Death pose

Dinosaur and bird fossils are frequently found in a characteristic posture consisting of head thrown back, tail extended, and mouth wide open. The cause of this posture—sometimes called a "death pose"—has been a matter of scientific debate. Traditional explanations ranged from strong ligaments in the animal's neck desiccating and contracting to draw the body into the pose, to water currents randomly arranging the remains in the position.Faux and Padian suggested in 2007 that the live animal was suffering opisthotonus during its death throes, and that the pose is not the result of any post-mortem process at all. They also reject the idea of water as responsible for randomly arranging the bodies in a "death pose", as different parts of the body and the limbs can be in different directions, which they found unlikely to be the result of moving water. They also found that the claim that drying out of ligaments would make the position does not seem believable either.

Alicia Cutler and colleagues from Brigham Young University in Provo, Utah, think it is related to water. In 2012, paleontologists Achim G. Reisdorf and Michael Wuttke published a study regarding death poses. According to the conclusions of this study, the so-called "opisthotonic posture" is not the result of a cerebral illness creating muscle spasms, and also not of a rapid burial. Rather, peri-mortem submersion resulted in buoyancy that enabled the Ligamentum elasticum to pull the head and tail back.

Death rattle

Terminal respiratory secretions (or simply terminal secretions), known colloquially as a death rattle, are sounds often produced by someone who is near death as a result of fluids such as saliva and bronchial secretions accumulating in the throat and upper chest. Those who are dying may lose their ability to swallow and may have increased production of bronchial secretions, resulting in such an accumulation. Usually, two or three days earlier, the symptoms of approaching death can be observed as saliva accumulates in the throat, making it very difficult to take even a spoonful of water. Related symptoms can include shortness of breath and rapid chest movement. While death rattle is a strong indication that someone is near death, it can also be produced by other problems that cause interference with the swallowing reflex, such as brain injuries.It is sometimes misinterpreted as the sound of the person choking to death, or alternatively, that they are gargling.

Death trajectory

Death trajectory refers to the pattern of dying when a patient is given a projected death date with limited or no medical recourse for the remaining existence of the individual's life. The death trajectory is dependent on the cause of death, whether it is sudden death, chronic illness, or the steady decline in health due to senescence (aging). Death trajectory is analyzed in two separate aspects: duration and shape. Duration refers to the period of time a patient has to live, which can be anywhere from imminent death to several months. Shape refers to how that duration is then graphed. In other words, the shape is "the course of dying, its predictability, and whether death is expected or unexpected".

Dying trajectories were first studied in the 1960s by two researchers, Barney Glaser and Anselm Strauss, in an attempt to understand the end of human life from different ailments, including cancer.

Dignified death

Dignified death is a somewhat elusive concept often related to suicide. One factor that has been cited as a core component of dignified death is maintaining a sense of control. Another view is that a truly dignified death is an extension of a dignified life. There is some concern that assisted suicide does not guarantee a dignified death, since some patients may experience complications such as nausea and vomiting. There is some concern that age discrimination denies the elderly a dignified death.


In medicine, dysthanasia means "bad death" and is considered a common fault of modern medicine.Dysthanasia occurs when a person who is dying has their biological life extended through technological means without regard to the person's quality of life. Technologies such as an implantable cardioverter defibrillator, artificial ventilation, ventricular assist devices, and extracorporeal membrane oxygenation can extend the dying process.

Dysthanasia is a term generally used when a person is seen to be kept alive artificially in a condition where, otherwise, they cannot survive; sometimes for some sort of ulterior motive. The term was used frequently in the investigation into the death of Formula One driver Ayrton Senna in 1994.

Lazarus sign

The Lazarus sign or Lazarus reflex is a reflex movement in brain-dead or brainstem failure patients, which causes them to briefly raise their arms and drop them crossed on their chests (in a position similar to some Egyptian mummies). The phenomenon is named after the Biblical figure Lazarus of Bethany, whom Jesus raised from the dead in the Gospel of John.


Megadeath (or megacorpse) is one million human deaths, usually caused by a nuclear explosion. The term was used by scientists and thinkers who strategized likely outcomes of all-out nuclear warfare.


A necronym (from the Greek words νεκρός, nekros, "dead" and ὄνομα ónoma, "name") is a reference to, or name of, a person who has died. Many cultures have taboos and traditions associated with referring to such a person. These vary from the extreme of never again speaking the person's real name, often using some circumlocution instead, to the opposite extreme of commemorating it incessantly by naming other things or people after the deceased.

For instance, in some cultures it is common for a newborn child to receive the name (a necronym) of a relative who has recently died, while in others to reuse such a name would be considered extremely inappropriate or even forbidden. While this varies from culture to culture, the use of necronyms is quite common.


Necrophobia is a specific phobia which is the irrational fear of dead things (e.g., corpses) as well as things associated with death (e.g., coffins, tombstones, funerals, cemeteries). With all types of emotions, obsession with death becomes evident in both fascination and objectification. In a cultural sense, necrophobia may also be used to mean a fear of the dead by a cultural group, e.g., a belief that the spirits of the dead will return to haunt the living.Symptoms include: shortness of breath, rapid breathing, irregular heartbeat, sweating, dry mouth and shaking, feeling sick and uneasy, psychological instability, and an altogether feeling of dread and trepidation. The sufferer may feel this phobia all the time. The sufferer may also experience this sensation when something triggers the fear, like a close encounter with a dead animal or the funeral of a loved one or friend. The fear may have developed when a person witnessed a death, or was forced to attend a funeral as a child. Some people experience this after viewing frightening media.The fear can manifest itself as a serious condition. Treatment options include medication and therapy.The word necrophobia is derived from the Greek nekros (νεκρός) for "corpse" and the Greek phobos (φόβος) for "fear".

Pallor mortis

Pallor mortis (Latin: pallor "paleness", mortis "of death"), the first stage of death, is an after-death paleness that occurs in those with light/white skin.

Post-mortem interval

Post-mortem interval (PMI) is the time that has elapsed since a person has died. If the time in question is not known, a number of medical/scientific techniques are used to determine it. This also can refer to the stage of decomposition of the body.


Promession is an idea of how to dispose human remains by way of freeze drying. The concept of promession was developed by Swedish biologist Susanne Wiigh-Mäsak, who derived the name from the Italian word for "promise" (promessa). She founded Promessa Organic AB in 1997 to commercially pursue her idea. The company was liquidated 2015 without being able to produce a functioning facility. The idea of promession is questioned and not a functional method according to critics.


Skeletonization refers to the final stage of decomposition, during which the last vestiges of the soft tissues of a corpse or carcass have decayed or dried to the point that the skeleton is exposed. By the end of the skeletonization process, all soft tissue will have been eliminated, leaving only disarticulated bones. In a temperate climate, it usually requires three weeks to several years for a body to completely decompose into a skeleton, depending on factors such as temperature, humidity, presence of insects, and submergence in a substrate such as water. In tropical climates, skeletonization can occur in weeks, while in tundra areas, skeletonization may take years or may never occur, if subzero temperatures persist. Natural embalming processes in peat bogs or salt deserts can delay the process indefinitely, sometimes resulting in natural mummification.The rate of skeletonization and the present condition of a corpse or carcass can be used to determine the time of death.After skeletonization, if scavenging animals do not destroy or remove the bones, acids in many fertile soils take about 20 years to completely dissolve the skeleton of mid- to large-size mammals, such as humans, leaving no trace of the organism. In neutral-pH soil or sand, the skeleton can persist for hundreds of years before it finally disintegrates. Alternately, especially in very fine, dry, salty, anoxic, or mildly alkaline soils, bones may undergo fossilization, converting into minerals that may persist indefinitely.

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