Regulation of cell death in cancer - possible implications for immunotherapy

Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is expected to open new perspectives for the development of novel experimental treatment strategies to enhance the efficacy of cancer immunotherapy in the future

Regulation of the programmed cell death protein 1/programmed cell death ligand 1 axis in relapsing-remitting multiple sclerosis

Tsaktanis et al. reveal distinct expression patterns of membrane-bound and soluble programmed cell death ligand 1 in relapsing-remitting multiple sclerosis, correlating with disease severity. These findings demonstrate regulation of programmed cell death protein 1/programmed cell death ligand 1 signalling and emphasize its potential as a disease surveillance and therapeutic target. The programmed cell death protein 1/programmed cell death ligand 1 axis plays an important role in the adaptive immune system and has influence on neoplastic and inflammatory diseases, while its role in multiple sclerosis is unclear. Here, we aimed to analyse expression patterns of programmed cell death protein 1 and programmed cell death ligand 1 on peripheral blood mononuclear cells and their soluble variants in multiple sclerosis patients and controls, to determine their correlation with clinical disability and disease activity. In a cross-sectional study, we performed in-depth flow cytometric immunophenotyping of peripheral blood mononuclear cells and analysed soluble programmed cell death protein 1 and programmed cell death ligand 1 serum levels in patients with relapsing-remitting multiple sclerosis and controls. In comparison to control subjects, relapsing-remitting multiple sclerosis patients displayed distinct cellular programmed cell death protein 1/programmed cell death ligand 1 expression patterns in immune cell subsets and increased soluble programmed cell death ligand 1 levels, which correlated with clinical measures of disability and MRI activity over time. This study extends our knowledge of how programmed cell death protein 1 and programmed cell death ligand 1 are expressed in the membranes of patients with relapsing-remitting multiple sclerosis and describes for the first time the elevation of soluble programmed cell death ligand 1 in the blood of multiple sclerosis patients. The distinct expression pattern of membrane-bound programmed cell death protein 1 and programmed cell death ligand 1 and the correlation between soluble programmed cell death ligand 1, membrane-bound programmed cell death ligand 1, disease and clinical factors may offer therapeutic potential in the setting of multiple sclerosis and might improve future diagnosis and clinical decision-making

Epigenetics and cell death: DNA hypermethylation in programmed retinal cell death.

BackgroundVertebrate genomes undergo epigenetic reprogramming during development and disease. Emerging evidence suggests that DNA methylation plays a key role in cell fate determination in the retina. Despite extensive studies of the programmed cell death that occurs during retinal development and degeneration, little is known about how DNA methylation might regulate neuronal cell death in the retina.MethodsThe developing chicken retina and the rd1 and rhodopsin-GFP mouse models of retinal degeneration were used to investigate programmed cell death during retinal development and degeneration. Changes in DNA methylation were determined by immunohistochemistry using antibodies against 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC).ResultsPunctate patterns of hypermethylation paralleled patterns of caspase3-dependent apoptotic cell death previously reported to occur during development in the chicken retina. Degenerating rd1 mouse retinas, at time points corresponding to the peak of rod cell death, showed elevated signals for 5mC and 5hmC in photoreceptors throughout the retina, with the most intense staining observed in the peripheral retina. Hypermethylation of photoreceptors in rd1 mice was associated with TUNEL and PAR staining and appeared to be cCaspase3-independent. After peak rod degeneration, during the period of cone death, occasional hypermethylation was observed in the outer nuclear layer.ConclusionThe finding that cell-specific increases of 5mC and 5hmC immunostaining are associated with the death of retinal neurons during both development and degeneration suggests that changes in DNA methylation may play a role in modulating gene expression during the process of retinal degeneration. During retinal development, hypermethylation of retinal neurons associates with classical caspase-dependent apoptosis as well as caspase-3 independent cell death, while hypermethylation in the rd1 mouse photoreceptors is primarily associated with caspase-3 independent programmed cell death. These findings suggest a previously unrecognized role for epigenetic mechanisms in the onset and/or progression of programed cell death in the retina

Reversal of an immunity associated plant cell death program by the growth regulator auxin

One form of plant immunity against pathogens involves a rapid host programmed cell death at the site of infection accompanied by resistance, termed the hypersensitive response (HR). Here it is shown that the HR programmed cell death program initiated by the bacterial type III secretion system dependent proteinaceous elicitor harpin from Erwinia amylovora can be reversed till very late in the process by the plant growth regulator auxin. Early inhibition or late reversal of this cell death program does not affect marker genes tightly correlated with local and systemic resistance. Cross-regulation between cell death programs and growth regulators is prevalent in different kingdoms. Thus, the concept that cell death program can be reversed till late provides a framework for further investigation of such phenomena, in addition to having utility in choosing better targets and strategies for treating mammalian and agricultural diseases

Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: A PRISMA systematic review and meta-analysis

Background: Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC. Methods: Articles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta. Results: Sixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22 (95 confidence interval CI, 17-28) for all grades and 4% (95% CI, 2-6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6-19.5 weeks) and varied depending on the organ system involved. Conclusions: The specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment. © 2019 The Author(s)

Apoptosis - Programmed Cell Death

Tijekom evolucije višestanični organizmi uspjeli su razviti različite mehanizme zaštite od djelovanja štetnih utjecaja iz okoline. Apoptoza ili “programirana smrt stanice” jedan je od tih mehanizama kojim stanica aktivno uz utrošak energije i sintezu određenih proteina pokreće vlastitu smrt kao sastavni dio fizioloških procesa ili kao odgovor na određena patološka stanja. Poremećaji u apoptozi vezani su uz mnogobrojne bolesti jer nefunkcionalne, mutirane ili na bilo koji način oštećene stanice koje izmaknu kontrolnim mehanizmima i koje ne obavljaju svoju fiziološku funkciju, mogu dovesti do pojave teških bolesti. Stoga je pravilan tijek apoptotskih procesa ključan za pravilan embrionalni razvoj i za pravilno održavanje stanične homeostaze tkiva. Centralno je mjesto apoptoze proenzimska skupina cisteinskih proteaza u citoplazmi stanica. Kaskadna aktivacija tih proteaza ključna je u genezi morfoloških i biokemijskih apoptotskih promjena. Do danas je već poznat velik broj vanjskih i unutarnjih faktora koji dovode do pojave apoptoze. Poznavanje tih faktora i puno razumijevanje mehanizama apoptotskih procesa otvara potpuno nove mogućnosti u liječenju nekih teških, zasad neizlječivih bolesti.During the evolution, multi-cellular organisms have developed various protective mechanisms against environmental insults. Apoptosis is one of physiological mechanisms where in fact a cell itself actively induces its own death. In contrast to necrosis where the cell death occurs usually as a result of severe physical or chemical extra cellular factors accompanied by inflammatory reactions of tissue, the apoptotic process starts without signs and symptoms of inflammation, and generally starts from the inside of the cell, involving the use of energy and active synthesis of specific proteins. Apoptosis is important for the right balance between the loss of old, non-functional cells and the formation of new ones in certain organs and tissues. In adition, it is a specific answer of an organism to a number of pathological conditions. Thus apoptosis plays a very important role both in physiologic and pathologic processes in the body throughout the life of an organism. A normal development of embryo and foetus is impossible without a very intensive apoptotic process. The dysfunction of the apoptotic mechanism is associated with a number of diseases in humans and animals. The apoptosis starts by triggering different intra- and intercellular signals and stimulations, which involve a number of extrinsic or intrinsic apoptotic pathways resulting in caspase cascade activation. Caspases belongs to the family of cisteine proteases, and have a central role in facilitating a number of morphological and biochemical changes during the programmed cell death. The understanding of these complex pathways offers new approaches to clinical treatment of fatal human diseases. The promising possibilities of application of the knowledge about the mechanism of apoptosis in the treatment of human diseases make the research in this field challenging and exciting

p53 directly regulates the glycosidase FUCA1 to promote chemotherapy-induced cell death

p53 is a central factor in tumor suppression as exemplified by its frequent loss in human cancer. p53 exerts its tumor suppressive effects in multiple ways, but the ability to invoke the eradication of damaged cells by programmed cell death is considered a key factor. The ways in which p53 promotes cell death can involve direct activation or engagement of the cell death machinery, or can be via indirect mechanisms, for example though regulation of ER stress and autophagy. We present here another level of control in p53-mediated tumor suppression by showing that p53 activates the glycosidase, FUCA1, a modulator of N-linked glycosylation. We show that p53 transcriptionally activates FUCA1 and that p53 modulates fucosidase activity via FUCA1 up-regulation. Importantly, we also report that chemotherapeutic drugs induce FUCA1 and fucosidase activity in a p53-dependent manner. In this context, while we found that over-expression of FUCA1 does not induce cell death, RNAi-mediated knockdown of endogenous FUCA1 significantly attenuates p53-dependent, chemotherapy-induced apoptotic death. In summary, these findings add an additional component to p53s tumor suppressive response and highlight another mechanism by which the tumor suppressor controls programmed cell death that could potentially be exploited for cancer therapy