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]


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  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.
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  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.
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