scholarly journals Cell Death in the Tumor Microenvironment: Implications for Cancer Immunotherapy

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2207
Author(s):  
Varsha Gadiyar ◽  
Kevin C. Lahey ◽  
David Calianese ◽  
Connor Devoe ◽  
Dhriti Mehta ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immune Escape ◽  
Apoptotic Cells ◽  
Phagocytic Cells ◽  
Purine Nucleotides ◽  
Compensatory Proliferation ◽  
Sphingosine 1 Phosphate ◽  
Homeostatic Function ◽  
Membrane Bound ◽  
Dying Cells

The physiological fate of cells that die by apoptosis is their prompt and efficient removal by efferocytosis. During these processes, apoptotic cells release intracellular constituents that include purine nucleotides, lysophosphatidylcholine (LPC), and Sphingosine-1-phosphate (S1P) that induce migration and chemo-attraction of phagocytes as well as mitogens and extracellular membrane-bound vesicles that contribute to apoptosis-induced compensatory proliferation and alteration of the extracellular matrix and the vascular network. Additionally, during efferocytosis, phagocytic cells produce a number of anti-inflammatory and resolving factors, and, together with apoptotic cells, efferocytic events have a homeostatic function that regulates tissue repair. These homeostatic functions are dysregulated in cancers, where, aforementioned events, if not properly controlled, can lead to cancer progression and immune escape. Here, we summarize evidence that apoptosis and efferocytosis are exploited in cancer, as well as discuss current translation and clinical efforts to harness signals from dying cells into therapeutic strategies.

scholarly journals Distinct Modes of Macrophage Recognition for Apoptotic and Necrotic Cells Are Not Specified Exclusively by Phosphatidylserine Exposure

2001 ◽  
Vol 12 (4) ◽  
pp. 919-930 ◽  
Author(s):  
Regina E. Cocco ◽  
David S. Ucker
Keyword(s):  
Macrophage Activation ◽  
Apoptotic Cells ◽  
Activated Macrophages ◽  
Necrotic Cell ◽  
Phagocytic Cells ◽  
Marked Contrast ◽  
Proinflammatory Responses ◽  
A Cell ◽  
Dying Cells ◽  
Specific Ligand

The distinction between physiological (apoptotic) and pathological (necrotic) cell deaths reflects mechanistic differences in cellular disintegration and is of functional significance with respect to the outcomes that are triggered by the cell corpses. Mechanistically, apoptotic cells die via an active and ordered pathway; necrotic deaths, conversely, are chaotic and passive. Macrophages and other phagocytic cells recognize and engulf these dead cells. This clearance is believed to reveal an innate immunity, associated with inflammation in cases of pathological but not physiological cell deaths. Using objective and quantitative measures to assess these processes, we find that macrophages bind and engulf native apoptotic and necrotic cells to similar extents and with similar kinetics. However, recognition of these two classes of dying cells occurs via distinct and noncompeting mechanisms. Phosphatidylserine, which is externalized on both apoptotic and necrotic cells, is not a specific ligand for the recognition of either one. The distinct modes of recognition for these different corpses are linked to opposing responses from engulfing macrophages. Necrotic cells, when recognized, enhance proinflammatory responses of activated macrophages, although they are not sufficient to trigger macrophage activation. In marked contrast, apoptotic cells profoundly inhibit phlogistic macrophage responses; this represents a cell-associated, dominant-acting anti-inflammatory signaling activity acquired posttranslationally during the process of physiological cell death.

Acid ceramidase, a double-edged sword in cancer aggression: A minireview

2020 ◽  
Vol 20 ◽  
Author(s):  
Helen Shiphrah Vethakanraj ◽  
Niveditha Chandrasekaran ◽  
Ashok Kumar Sekar
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Potential Role ◽  
Tumour Progression ◽  
Acid Ceramidase ◽  
The Core ◽  
The Past ◽  
Sphingosine 1 Phosphate ◽  
Key Enzyme

: Acid ceramidase (AC), the key enzyme of the ceramide metabolic pathway hydrolyzes pro-apoptotic ceramide to sphingosine, which by the action of sphingosine-1-kinase is metabolized to mitogenic sphingosine-1-phosphate. The intracellular level of AC determines ceramide/sphingosine-1-phosphate rheostat which in turn decides the cell fate. The upregulated AC expression during cancerous condition acts as a “double-edged sword” by converting pro-apoptotic ceramide to anti-apoptotic sphingosine-1-phosphate, wherein on one end, the level of ceramide is decreased and on the other end, the level of sphingosine-1-phosphate is increased, thus altogether aggravating the cancer progression. In addition, cancer cells with upregulated AC expression exhibited increased cell proliferation, metastasis, chemoresistance, radioresistance and numerous strategies were developed in the past to effectively target the enzyme. Gene silencing and pharmacological inhibition of AC sensitized the resistant cells to chemo/radiotherapy thereby promoting cell death. The core objective of this review is to explore AC mediated tumour progression and the potential role of AC inhibitors in various cancer cell lines/models.

scholarly journals PDIA6 promotes pancreatic cancer progression and immune escape through CSN5-mediated deubiquitination of β-catenin and PD-L1

Neoplasia ◽  
2021 ◽  
Vol 23 (9) ◽  
pp. 912-928
Author(s):  
Yihui Ma ◽  
Peiyi Xia ◽  
Zhengyang Wang ◽  
Jingjing Xu ◽  
Lan Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Immune Escape

scholarly journals Trends in Research on Exosomes in Cancer Progression and Anticancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 326
Author(s):  
Dona Sinha ◽  
Sraddhya Roy ◽  
Priyanka Saha ◽  
Nabanita Chatterjee ◽  
Anupam Bishayee
Keyword(s):  
Cancer Progression ◽  
Targeted Delivery ◽  
Cancer Biology ◽  
Vaccine Development ◽  
Immune Escape ◽  
Immune Therapy ◽  
Bioactive Molecules ◽  
Successful Implementation ◽  
Scale Production ◽  
Exosome Biogenesis

Exosomes, the endosome-derived bilayered extracellular nanovesicles with their contribution in many aspects of cancer biology, have become one of the prime foci of research. Exosomes derived from various cells carry cargoes similar to their originator cells and their mode of generation is different compared to other extracellular vesicles. This review has tried to cover all aspects of exosome biogenesis, including cargo, Rab-dependent and Rab-independent secretion of endosomes and exosomal internalization. The bioactive molecules of the tumor-derived exosomes, by virtue of their ubiquitous presence and small size, can migrate to distal parts and propagate oncogenic signaling and epigenetic regulation, modulate tumor microenvironment and facilitate immune escape, tumor progression and drug resistance responsible for cancer progression. Strategies improvised against tumor-derived exosomes include suppression of exosome uptake, modulation of exosomal cargo and removal of exosomes. Apart from the protumorigenic role, exosomal cargoes have been selectively manipulated for diagnosis, immune therapy, vaccine development, RNA therapy, stem cell therapy, drug delivery and reversal of chemoresistance against cancer. However, several challenges, including in-depth knowledge of exosome biogenesis and protein sorting, perfect and pure isolation of exosomes, large-scale production, better loading efficiency, and targeted delivery of exosomes, have to be confronted before the successful implementation of exosomes becomes possible for the diagnosis and therapy of cancer.

Computational study for suppression of CD25/IL-2 interaction

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Moein Dehbashi ◽  
Zohreh Hojati ◽  
Majid Motovali-bashi ◽  
Mazdak Ganjalikhani-Hakemi ◽  
Akihiro Shimosaka ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cancer Progression ◽  
Immune Escape ◽  
De Novo ◽  
Computational Study ◽  
Treg Cells ◽  
Homology Search ◽  
Small Interfering Rnas

AbstractCancer recurrence presents a huge challenge in cancer patient management. Immune escape is a key mechanism of cancer progression and metastatic dissemination. CD25 is expressed in regulatory T (Treg) cells including tumor-infiltrating Treg cells (TI-Tregs). These cells specially activate and reinforce immune escape mechanism of cancers. The suppression of CD25/IL-2 interaction would be useful against Treg cells activation and ultimately immune escape of cancer. Here, software, web servers and databases were used, at which in silico designed small interfering RNAs (siRNAs), de novo designed peptides and virtual screened small molecules against CD25 were introduced for the prospect of eliminating cancer immune escape and obtaining successful treatment. We obtained siRNAs with low off-target effects. Further, small molecules based on the binding homology search in ligand and receptor similarity were introduced. Finally, the critical amino acids on CD25 were targeted by a de novo designed peptide with disulfide bond. Hence we introduced computational-based antagonists to lay a foundation for further in vitro and in vivo studies.

Topics in Chronic Granulomatous Disease

PEDIATRICS ◽  
1991 ◽  
Vol 88 (1) ◽  
pp. 183-185
Author(s):  
SHIGENOBU UMEKI
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Host Defense ◽  
Superoxide Anion ◽  
Fungal Infections ◽  
Regulatory Elements ◽  
Granulomatous Disease ◽  
Phagocytic Cells ◽  
Oxidase System ◽  
Membrane Bound

To the Editor.— Such phagocytic cells as neutrophils and macrophages are crucial elements in the host defense against bacterial [See table in the PDF file] and fungal infections. Microbicidal activity depends to a large extent on NADPH oxidase system, which can be activated by stimuli (bacteria, fungi) and which generates the superoxide anion and other highly reactive forms of reduced oxygen.1,2 The neutrophil NADPH oxidase system is composed functionally of membrane-bound catalytic components (which consist of at least two constituents, the low potential cytochrome b5583-5 and flavoprotein5) and soluble cytosolic components6,7 which participate as either catalytic or regulatory elements.

scholarly journals Chemokines as phosphatidylserine-bound ‘find-me’ signals in apoptotic cell clearance

2020 ◽  
Author(s):  
Sergio M. Pontejo ◽  
Philip M. Murphy
Keyword(s):  
Extracellular Vesicles ◽  
Chemokine Receptors ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Anionic Phospholipid ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Cell Plasma ◽  
Signal Activity ◽  
Dying Cells

AbstractChemokines are positively charged cytokines that attract leukocytes by binding to anionic glycosaminoglycans (GAGs) on endothelial cells for efficient presentation to leukocyte G protein-coupled receptors (GPCRs). The atypical chemokine CXCL16 has been reported to also bind the anionic phospholipid phosphatidylserine (PS), but the biological relevance of this interaction remains poorly understood. Here we demonstrate that PS binding is in fact a widely shared property of chemokine superfamily members that, like GAG binding, induces chemokine oligomerization. PS is an essential phospholipid of the inner leaflet of the healthy cell plasma membrane but it is exposed in apoptotic cells to act as an ‘eat-me’ signal that promotes engulfment of dying cells by phagocytes. We found that chemokines can bind PS in pure form as well as in the context of liposomes and on the surface of apoptotic cells and extracellular vesicles released by apoptotic cells, which are known to act as ‘find-me’ signals that chemoattract phagocytes during apoptotic cell clearance. Importantly, we show that GAGs are severely depleted from the surface of apoptotic cells and that extracellular vesicles extracted from apoptotic mouse thymus bind endogenous thymic chemokines and activate cognate chemokine receptors. Together these results indicate that chemokines tethered to surface-exposed PS may be responsible for the chemotactic and find-me signal activity previously attributed to extracellular vesicles, and that PS may substitute for GAGs as the anionic scaffold that regulates chemokine oligomerization and presentation to GPCRs on the GAG-deficient membranes of apoptotic cells and extracellular vesicles. Here, we present a new mechanism by which extracellular vesicles, currently recognized as essential agents for intercellular communication in homeostasis and disease, can transport signaling cytokines.

scholarly journals Overexposure to apoptosis via disrupted glial specification perturbs Drosophila macrophage function and reveals roles of the CNS during injury

2020 ◽  
Author(s):  
Emma Louise Armitage ◽  
Hannah Grace Roddie ◽  
Iwan Robert Evans
Keyword(s):  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Calcium Waves ◽  
Apoptotic Cells ◽  
Phagocytic Cells ◽  
Macrophage Function ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Wound Responses

AbstractApoptotic cell clearance by phagocytes is a fundamental process during development, homeostasis and the resolution of inflammation. However, the demands placed on phagocytic cells such as macrophages by this process, and the limitations these interactions impose on subsequent cellular behaviours are not yet clear. Here we seek to understand how apoptotic cells affect macrophage function in the context of a genetically-tractable Drosophila model in which macrophages encounter excessive amounts of apoptotic cells. We show that loss of the glial transcription factor repo, and corresponding removal of the contribution these cells make to apoptotic cell clearance, causes macrophages in the developing embryo to be challenged with large numbers of apoptotic cells. As a consequence, macrophages become highly vacuolated with cleared apoptotic cells and their developmental dispersal and migration is perturbed. We also show that the requirement to deal with excess apoptosis caused by a loss of repo function leads to impaired inflammatory responses to injury. However, in contrast to migratory phenotypes, defects in wound responses cannot be rescued by preventing apoptosis from occurring within a repo mutant background. In investigating the underlying cause of these impaired inflammatory responses, we demonstrate that wound-induced calcium waves propagate into surrounding tissues, including neurons and glia of the ventral nerve cord, which exhibit striking calcium waves on wounding, revealing a previously unanticipated contribution of these cells during responses to injury. Taken together these results demonstrate important insights into macrophage biology and how repo mutants can be used to study macrophage-apoptotic cell interactions in the fly embryo.Furthermore, this work shows how these multipurpose cells can be ‘overtasked’ to the detriment of their other functions, alongside providing new insights into which cells govern macrophage responses to injury in vivo.

scholarly journals The Importance of Exosomal PD-L1 in Cancer Progression and Its Potential as a Therapeutic Target

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3247
Author(s):  
Lingxiao Ye ◽  
Zhengxin Zhu ◽  
Xiaochuan Chen ◽  
Haoran Zhang ◽  
Jiaqi Huang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Progression ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Escape ◽  
Tumor Treatment

Binding of programmed cell death ligand 1 (PD-L1) to its receptor programmed cell death protein 1 (PD-1) can lead to the inactivation of cytotoxic T lymphocytes, which is one of the mechanisms for immune escape of tumors. Immunotherapy based on this mechanism has been applied in clinic with some remaining issues such as drug resistance. Exosomal PD-L1 derived from tumor cells is considered to play a key role in mediating drug resistance. Here, the effects of various tumor-derived exosomes and tumor-derived exosomal PD-L1 on tumor progression are summarized and discussed. Researchers have found that high expression of exosomal PD-L1 can inhibit T cell activation in in vitro experiments, but the function of exosomal PD-L1 in vivo remains controversial. In addition, the circulating exosomal PD-L1 has high potential to act as an indicator to evaluate the clinical effect. Moreover, therapeutic strategy targeting exosomal PD-L1 is discussed, such as inhibiting the biogenesis or secretion of exosomes. Besides, some specific methods based on the strategy of inhibiting exosomes are concluded. Further study of exosomal PD-L1 may provide an effective and safe approach for tumor treatment, and targeting exosomal PD-L1 by inhibiting exosomes may be a potential method for tumor treatment.

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