Nature: to reveal the mechanism of cytokine storm induced by catecholamine in immunotherapy

January 29, 2020 / Biovalley BIOON / - -- many newly developed powerful cancer therapies aim to utilize immune response targeting tumor However, a common problem of this kind of immunotherapy is the occurrence of severe inflammatory reaction, namely, the cytokine storm In cytokine storms, levels of proteins called cytokines are abnormally high This can lead to fever, hypotension, heart problems, and, in some cases, organ failure and death Therefore, it is of great interest to understand the internal mechanism of cytokine storm formation so as to develop methods to prevent it without changing the therapeutic effect of anti-cancer treatment In a new study, researchers from the Kimmel Cancer Center at Johns Hopkins University and the Johns Hopkins University School of medicine in the United States revealed the protein ANP, Atrial natriuretic peptide) can block cytokine storms, and they found a self expanding production loop in immune cells, which produces a group of molecules called catecholamines, including adrenaline They report that this catecholamine production helps initiate and sustain cytokine storms The relevant research results were recently published in the journal Nature, and the title of the paper is "disruption of a self-sustaining catalamine loop reductions cytokine release syndrome" Picture from nature, DOI: 10.1038/s41586-018-0774-y When immune cells recognize molecules that indicate potential threats, they release cytokines that promote inflammation and coordinate host defense One anti-tumor therapy that triggers cytokine storms is the use of a bacterium called Clostridium novyi NT, which can track the low oxygen environment found in certain tumors and release spores that cause tumor cell death It is difficult to determine the correct bacterial dose, and mice with large tumors receiving high doses of Clostridium norvegicum NT often produce lethal cytokine storms that cannot be prevented by the use of inhibitors that block the action of cytokines or their receptors In order to determine whether some known anti-inflammatory proteins can prevent cytokine storms, the researchers genetically engineered Clostridium norvegicum nt to secrete anti-inflammatory proteins, and tested whether they can effectively treat tumors in mice without causing serious side effects due to high cytokine levels Their experiments show that ANP can inhibit cytokine storm Compared with mice fed with ANP expressing NT, mice fed with ANP expressing NT had lower levels of pro-inflammatory molecules (including cytokines) in their blood and lower levels of immune cell infiltration associated with cytokine storms called myeloid cells To determine how ANP reduces cytokine storms in model systems, the researchers described differences between mice treated with ANP expressing Clostridium norvegicum nt and mice treated with non genetically modified bacteria This suggests that decreased ANP related immune response is accompanied by a decrease in catecholamine levels in the blood of these mice Catecholamines, such as epinephrine, are known for their role in the fight or flight response to acute stress Some neurons and adrenals release catecholamine in the fight or flight response The idea that catecholamines may play a role in promoting cytokine storms seems counterintuitive, because such molecules are often used to treat hypotension associated with cytokine storms However, it is well known that two immune cells, macrophages and neutrophils, react to inflammatory stimuli such as lipopolysaccharide (LPS) to produce catecholamine, which is a marker of many bacterial infections To find out if catecholamine might play a key role in driving a strong inflammatory response, the researchers gave mice lipopolysaccharides and adrenaline to some of them Compared with mice receiving only lipopolysaccharide, mice receiving adrenaline and lipopolysaccharide had higher cytokine levels and mortality In contrast, when they provided lipopolysaccharides to mice genetically engineered to lack tyrosine hydroxylase, the enzyme needed to make catecholamine, they had a higher survival rate, lower cytokine and catecholamine levels than mice receiving lipopolysaccharide with intact tyrosine hydroxylase When they treated mice with drugs that blocked catecholamine receptors called alpha-1 adrenergic receptors, the drug blocked inflammation in mice treated with lipopolysaccharide compared with mice not treated with lipopolysaccharide The researchers also confirmed that catecholamines play an important role in cytokine storms caused by bacteria in different models of severe bacterial infection In both cases, they found lower catecholamine and cytokine levels and increased survival compared with mice that did not receive methyltyrosine, a drug that inhibits tyrosine hydroxylase The next key question is whether catecholamine release plays a role in cytokine storms caused by activation of immune cells due to non-contact bacteria Catecholamines are also produced by T cells that trigger an immune response The purpose of some immunotherapies is to produce activated T cells by giving antibodies that activate T cells or by introducing T cells that are genetically engineered to target tumor cells (called chimeric antigen receptor T cells, car-t) All of these methods can cause cytokine storm To test whether catecholamine might play a role in this cytokine storm, the researchers administered t-cell-activated antibodies to a group of mice, as well as methyltyrosine to some of them Compared with the mice without methionine, the mice receiving methionine had higher survival rate and lower cytokine level The researchers then cultured human car-t cells in vitro with the type of blood cancer cells that activated them The medium in this cell culture contains catecholamine and cytokines If adrenaline is added to this cell culture, the level of these molecules will increase, which provides support for the self amplification reaction model to promote catecholamine production The researchers continued to give car-t cells to mice carrying tumors Prior to the administration of car-t cells, some of the mice were provided with ANP or methyltyrosine, and their cytokine levels were lower than those of the mice receiving car-t cells only However, this difference does not affect the efficiency of anti-tumor treatment, which indicates that the side effects caused by cytokines are not related to the anti-tumor effect of this treatment These researchers provide convincing evidence that the self expanding loop of catecholamine released by immune cells initiates cytokine storms However, determining the details of such a loop will require further study For example, how the activation of immune cells can promote the increase of catecholamine level and how catecholamine can promote the production of cytokines are unknown and should be studied Another mystery is which type of adrenergic receptor is critical to the effect of catecholamine on human cytokine levels ANP has anti-inflammatory properties, but how it can inhibit the production of catecholamine is another unsolved key problem, which deserves further research These findings may lead to the development of new strategies to deal with cytokine storms in immunotherapy The mouse model of car-t cell immunotherapy shows that the activation of myeloid cells plays a key role in driving cytokine storm - it may be effective to prevent cytokine storm by preventing some cytokines or their receptors from acting in advance through antibodies or other methods However, these researchers have now identified the important role of catecholamine production in cytokine storm, and have shown that ANP and methyltyrosine, which have been approved for use in other clinical environments, may effectively prevent this complication It is generally believed that the production of cytokines and their role in the activation of immune cells contribute to improving the efficiency of anti-tumor immune response In order to ensure that the anti-tumor effect will not be weakened, it is necessary to be cautious in clinical testing whether targeted catecholamine synthesis can reduce cytokine storm (bio Com) reference: 1 Verena staedtke et al Disruption of a self amplifying catalyst loop reductions cytokine release syndrome Nature, 2019, DOI: 10.1038/s41586-018-0774-y 2 Adaptive fuels a cytokine store during immutability https://w w w.nature.com/articles/d41586-018-07581-w