#ULTIMATE SURRENDER PROFESSIONAL#
Extracellular ATP functions as a “find-me” signal for professional phagocytes and has additional immunostimulatory effects through inflammasome activation. Such PRRs include Toll-like receptors (TLR) 2 and 4, which recognize the disulfide form of HMGB1 and activate specific transcriptional and post-transcriptional inflammatory responses. HMGB1 has several redox states, each of which can bind to several pattern recognition receptors (PRRs) expressed on antigen presenting cells (APCs). HMGB1 is the archetypal DAMP associated with inflammatory responses and is released late during ICD. Calreticulin is one of the most abundant proteins in the ER lumen but progresses anterogradely to secretion during ICD by binding to the surface of the dying cell it signals “eat me” to professional phagocytes. įollowing UPR activation, cells undergoing ICD release damage-associated molecular patterns (DAMPs) such as calreticulin, heat shock proteins (HSPs), High Mobility Group Box 1 (HMGB1), and ATP (and others as the context dictates). The characteristic feature of ICD is the activation of the PERK arm of the UPR, which itself is an attempt to react to ER stress: PERK is a kinase (eukaryotic translation-initiation factor 2-alpha kinase 3, EIF2AK3) that is integral to the ER membrane and, as its name implies, phosphorylates and inactivates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to a rapid decrease of global protein synthesis. Some ICD inducers cause ER stress directly, but others cause DNA or chromatin damage, which then initiate ER stress via crosstalk between the DNA damage response (DDR) and the unfolded protein response (UPR). The common upstream event in ICD is endoplasmic reticulum (ER) stress with high production of reactive oxygen species (ROS). Cells that undergo ICD might be targeted by pathogens (including some viruses) or chemotherapeutic agents. ICD is characterized by apoptotic morphology with the retention of membrane integrity. ICD has been recently defined as “a form of regulated cell death that is sufficient to activate an adaptive immune response in immunocompetent syngeneic hosts”. We will argue that ICD and immunogenic surrender are related but distinct biological processes. Recently, we described “immunogenic surrender”, another mechanism that promotes anti-cancer immune responses. If the appearance of neoantigens per se is not the tripwire to kick-start immune responses, what is? This was first answered by the recognition of immunogenic cell death (ICD), a special type of cell death that triggers anti-cancer immune responses against cell neoantigens. Arguably, cells or exosomes bearing neoantigens are not sufficient to elicit a durable immune response in fact, the same mutational mechanisms generate neoantigens in cancer cells and in aging cells, and yet most aged somatic cells escape the recognition and elimination by the immune system. Dendritic cells sample the microenvironment by phagocytosing exosomes released by living cells or apoptotic bodies deriving from apoptotic cells, and will cross-present new epitopes these contain. If antigens are not detected by the immune system, no immune responses can take place. However, the selection and expansion of such cytotoxic T lymphocyte clones depend on tumor antigen cross-presentation and T cell priming in the first place. Current immunotherapies focus on disabling the PD-1 or CTLA-4 systems, which restrain the activity of cytotoxic T lymphocytes that recognize tumor neoantigens. The success of immunotherapies has demonstrated to what extent the immune system can detect, keep in check, and sometimes reverse the development of cancer.