scholarly journals Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Hatem Tallima ◽  
Hassan M. E. Azzazy ◽  
Rashika El Ridi
Keyword(s):  
Cell Surface ◽  
Immune Evasion ◽  
Immune Escape ◽  
Surface Membrane ◽  
Killer Cell ◽  
Biochemical Changes ◽  
Contact Inhibition ◽  
Cell Contact ◽  
Tumor Immune Escape ◽  
Cancer Initiation

AbstractCell surface biochemical changes, notably excessive increase in outer leaflet sphingomyelin (SM) content, are important in cancer initiation, growth, and immune evasion. Innumerable reports describe methods to initiate, promote, or enhance immunotherapy of clinically detected cancer, notwithstanding the challenges, if not impossibility, of identification of tumor-specific, or associated antigens, the lack of tumor cell surface membrane expression of major histocompatibility complex (MHC) class I alpha and β2 microglobulin chains, and lack of expression or accessibility of Fas and other natural killer cell immune checkpoint molecules. Conversely, SM synthesis and hydrolysis are increasingly implicated in initiation of carcinogenesis and promotion of metastasis. Surface membrane SM readily forms inter- and intra- molecular hydrogen bond network, which excessive tightness would impair cell-cell contact inhibition, inter- and intra-cellular signals, metabolic pathways, and susceptibility to host immune cells and mediators. The present review aims at clarifying the tumor immune escape mechanisms, which face common immunotherapeutic approaches, and attracting attention to an entirely different, neglected, key aspect of tumorigenesis associated with biochemical changes in the cell surface that lead to failure of contact inhibition, an instrumental tumorigenesis mechanism. Additionally, the review aims to provide evidence for surface membrane SM levels and roles in cells resistance to death, failure to respond to growth suppressor signals, and immune escape, and to suggest possible novel approaches to cancer control and cure.

scholarly journals Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 926 ◽  
Author(s):  
Stefania Mantovani ◽  
Barbara Oliviero ◽  
Stefania Varchetta ◽  
Dalila Mele ◽  
Mario U. Mondelli
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Escape ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Current Status ◽  
Tumor Immune Escape

Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

scholarly journals Current Progress in Cancer Immunotherapies Using Small Molecules Targeting PD-L1 Stability

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Macyn Leung ◽  
Alexander Pipchuk ◽  
Xiaolong Yang ◽  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Immune Escape ◽  
Immune Checkpoint Blockade ◽  
Tumor Immune Escape ◽  
Tumor Immune Evasion ◽  
L1 Stability

PD-L1 is an immune checkpoint protein that is frequently overexpressed by the cells in the tumor microenvironment. PD-L1 binds to PD-1 present on the activated antitumor T-cells, which allows for tumor immune escape. The ability of the PD-1/PD-L1 axis to suppress antitumor immunity enables its application as a potential target for small-molecule-based immunotherapies. Targeting the PD-L1-mediated tumor immune evasion represents a promising approach for immune checkpoint blockade therapies. However, the existing monoclonal antibody-based therapies present poor overall response rates, warranting the development of small molecule drugs with the ability to regulate PD-L1 stability and enhance antitumor immunity. In this context, the present review summarizes the mechanisms of upstream PD-L1 regulation by kinases, cell cycle modulators, ubiquitin ligases, and glycosylation modulators, as well as the efficacy of small molecules targeting PD-L1 stability in regulating PD-L1-mediated immune evasion.

scholarly journals Selective Expression of Variant Surface Antigens Enables Plasmodium falciparum to Evade Immune Clearance in vivo

2020 ◽  
Author(s):  
Marvin Chew ◽  
Weijian Ye ◽  
Radoslaw Igor Omelianczyk ◽  
Charisse Flerida Pasaje ◽  
Regina Hoo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Evasion ◽  
Immune Escape ◽  
Killer Cell ◽  
Surface Antigens ◽  
Variant Surface Antigens ◽  
Immune Clearance ◽  
Macrophage Phagocytosis

AbstractPlasmodium falciparum has developed extensive mechanisms to evade host immune clearance. Currently, most of our understanding is based on in vitro studies of individual parasite variant surface antigens and how this relates to the processes in vivo is not well-understood. Here, we have used a humanized mouse model to identify parasite factors important for in vivo growth. We show that upregulation of the specific PfEMP1, VAR2CSA and the RIFIN PF3D7_1254800 provides the parasite with protection from macrophage phagocytosis and natural killer cell mediated killing. Taken together, these findings reveal new insights on the molecular and cellular mechanisms that coordinate the immune escape process the parasite utilizes in vivo. As immune evasion may be particularly important during the establishment of the blood stage infection when parasite numbers are still relatively small, identification of specific parasite variant surface antigens provides targets for developing more effective vaccines by targeting parasite immune evasion.

scholarly journals Immunohistochemical localization of cellCAM 105 in rat tissues: appearance in epithelia, platelets, and granulocytes.

1988 ◽  
Vol 36 (7) ◽  
pp. 729-739 ◽  
Author(s):  
P Odin ◽  
M Asplund ◽  
C Busch ◽  
B Obrink
Keyword(s):  
Cell Surface ◽  
Plasma Membranes ◽  
Surface Membrane ◽  
Cell Types ◽  
Cell Contact ◽  
Rat Tissues ◽  
Common Denominator ◽  
Surface Distribution ◽  
Organ Systems ◽  
Cell Cell

CellCAM 105 is an integral membrane glycoprotein, with apparent Mr 105,000, which has been purified from rat liver plasma membranes. It consists of two structurally similar, highly glycosylated polypeptide chains and is involved in cell-cell adhesion of adult rat hepatocytes in vitro. In this communication we report on the distribution and cell surface location of cellCAM 105 in rat tissues, obtained by using highly sensitive immunodetection systems based on complex formation between biotinylated antibodies, biotinylated peroxidase and avidin, or on antibodies coupled to alkaline phosphatase. CellCAM was found in many organs and organ systems, including liver, kidney, blood, blood vessels, glands, respiratory system, and gastrointestinal tract. It was mainly localized to epithelial structures but showed a varying cell surface distribution. In some cell types it was predominantly localized to cell-cell contact areas. In other cell types the highest concentrations were seen in brush-border areas containing densely packed microvilli. In addition to epithelial structures, cellCAM 105 was found in rat platelets, where it became strongly expressed on the cell surfaces after activation with ADP or collagen, suggesting that it might be involved in platelet adhesion and/or aggregation mechanisms. Granulocytes also contained cellCAM 105. By SDS-PAGE/immunoblotting, significant differences were found in the apparent Mr values of cellCAM 105 in different tissues. The collected data suggest that cellCAM 105 participates in several different cell surface membrane interactions, of which the common denominator might be membrane-membrane binding.

scholarly journals Curcumin as an Adjuvant to Cancer Immunotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Silpita Paul ◽  
Gaurisankar Sa
Keyword(s):  
Immune Evasion ◽  
Immune Escape ◽  
Growth Inhibitors ◽  
Invasion And Metastasis ◽  
Hallmarks Of Cancer ◽  
Tumor Immune Escape ◽  
Tissue Invasion ◽  
Anti Cancer ◽  
Immune Adjuvant ◽  
Over Time

The components of the immune system play a very sincere and crucial role in combating tumors. However, despite their firm efforts of elimination, tumor cells cleverly escape the surveillance process by adopting several immune evasion mechanisms. The conversion of immunogenicity of tumor microenvironment into tolerogenic is considered as a prime reason for tumor immune escape. Therapeutically, different immunotherapies have been adopted to block such immune escaping routes along with better clinical outcomes. Still, the therapies are haunted by several drawbacks. Over time, curcumin has been considered as a potential anti-cancer molecule. Its potentialities have been recorded against the standard hallmarks of cancer such as continuous proliferation, escaping apoptosis, continuous angiogenesis, insensitivity to growth inhibitors, tissue invasion, and metastasis. Hence, the diversity of curcumin functioning has already been established and exploration of its application with immunotherapies might open up a new avenue for scientists and clinicians. In this review, we briefly discuss the tumor’s way of immune escaping, followed by various modern immunotherapies that have been used to encounter the escaping paths and their minute flaws. Finally, the conclusion has been drawn with the application of curcumin as a potential immune-adjuvant, which fearlessly could be used with immunotherapies for best outcomes.

scholarly journals Next frontier in tumor immunotherapy: macrophage-mediated immune evasion

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Yingqi Qiu ◽  
Tong Chen ◽  
Rong Hu ◽  
Ruiyi Zhu ◽  
Chujun Li ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Immune Escape ◽  
Tumor Immunotherapy ◽  
Immune Checkpoints ◽  
Cancer Treatments ◽  
Tumor Immune Escape ◽  
Tumor Immune Evasion ◽  
New Ideas ◽  
And Function ◽  
Immunosuppressive Cells

AbstractTumor-associated macrophages (TAMs), at the core of immunosuppressive cells and cytokines networks, play a crucial role in tumor immune evasion. Increasing evidences suggest that potential mechanisms of macrophage-mediated tumor immune escape imply interpretation and breakthrough to bottleneck of current tumor immunotherapy. Therefore, it is pivotal to understand the interactions between macrophages and other immune cells and factors for enhancing existing anti-cancer treatments. In this review, we focus on the specific signaling pathways through which TAMs involve in tumor antigen recognition disorders, recruitment and function of immunosuppressive cells, secretion of immunosuppressive cytokines, crosstalk with immune checkpoints and formation of immune privileged sites. Furthermore, we summarize correlative pre-clinical and clinical studies to provide new ideas for immunotherapy. From our perspective, macrophage-targeted therapy is expected to be the next frontier of cancer immunotherapy.

scholarly journals Leveraging NKG2D Ligands in Immuno-Oncology

2021 ◽  
Vol 12 ◽  
Author(s):  
Mercedes Beatriz Fuertes ◽  
Carolina Inés Domaica ◽  
Norberto Walter Zwirner
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Immune Escape ◽  
Nk Cell ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Combination Therapies ◽  
Tumor Immune Escape ◽  
Effector Functions ◽  
Immune Escape Mechanisms

Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.

Influence of Calcium Ions on the Plant Cell Surface: Membrane Fusions and Conformational Changes

1974 ◽  
Vol 32 ◽  
pp. 154-155
Author(s):  
D. James Morré ◽  
Charles E. Bracker ◽  
William J. VanDerWoude
Keyword(s):  
Cell Wall ◽  
Cell Surface ◽  
Conformational Changes ◽  
Calcium Ions ◽  
Surface Membrane ◽  
Carboxyl Groups ◽  
Cross Linking ◽  
Ultrastructural Evidence ◽  
Glycine Max L ◽  
Wall Extensibility

Calcium ions in the concentration range 5-100 mM inhibit auxin-induced cell elongation and wall extensibility of plant stems. Inhibition of wall extensibility requires that the tissue be living; growth inhibition cannot be explained on the basis of cross-linking of carboxyl groups of cell wall uronides by calcium ions. In this study, ultrastructural evidence was sought for an interaction of calcium ions with some component other than the wall at the cell surface of soybean (Glycine max (L.) Merr.) hypocotyls.

Oncornavirus assembly at the cell surface revealed in replicas of freeze-dried cells

1978 ◽  
Vol 36 (2) ◽  
pp. 354-355
Author(s):  
Anthony Demsey ◽  
Christopher W. Stackpole
Keyword(s):  
Cell Surface ◽  
Surface Membrane ◽  
Viral Origin ◽  
Intact Cells ◽  
Structural Formation ◽  
Virus Core ◽  
Freeze Dried ◽  
Cacodylate Buffer ◽  
Surface Replica ◽  
Leukemia Viruses

The murine leukemia viruses are type-C oncornaviruses, and their release from the host cell involves a “budding” process in which the newly-forming, RNA-containing virus core becomes enveloped by modified cell surface membrane. Previous studies revealed that the released virions possess a dense array of 10 nm globular projections (“knobs”) on this envelope surface, and that these knobs contain a 70, 000 MW glycoprotein (gp70) of viral origin. Taking advantage of this distinctive structural formation, we have developed a procedure for freeze-drying and replication of intact cells which reveals surface detail superior to other surface replica techniques, and sufficient to detect even early stages of virus budding by localized aggregation of these knobs on the cell surface.Briefly, cells growing in monolayer are seeded onto round glass coverslips 10-12 mm in diameter. After a period of growth, cells are fixed in situ for one hour, usually with 1% OsO4 in 0. 1 M cacodylate buffer, and rinsed in distilled water.

The organization of cell surface membrane domains

1989 ◽  
Vol 47 ◽  
pp. 804-805
Author(s):  
Michael Edidin
Keyword(s):  
Cell Surface ◽  
Membrane Lipids ◽  
Surface Membrane ◽  
Lateral Diffusion ◽  
Cell Types ◽  
Membrane Domains ◽  
Membrane Biology ◽  
Morphological Polarity ◽  
Discrete Domains ◽  
Membrane Components

Cell surface membranes are based on a fluid lipid bilayer and models of the membranes' organization have emphasised the possibilities for lateral motion of membrane lipids and proteins within the bilayer. Two recent trends in cell and membrane biology make us consider ways in which membrane organization works against its inherent fluidity, localizing both lipids and proteins into discrete domains. There is evidence for such domains, even in cells without obvious morphological polarity and organization [Table 1]. Cells that are morphologically polarised, for example epithelial cells, raise the issue of membrane domains in an accute form.The technique of fluorescence photobleaching and recovery, FPR, was developed to measure lateral diffusion of membrane components. It has also proven to be a powerful tool for the analysis of constraints to lateral mobility. FPR resolves several sorts of membrane domains, all on the micrometer scale, in several different cell types.

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