Hypoxia-inducible factor 1 (HIF-1) plays an indispensable role in the hypoxic tumor microenvironment. Hypoxia and HIF-1 are involved in multiple aspects of tumor progression, such as metastasis, angiogenesis, and immune evasion. In innate and adaptive immune systems, malignant tumor cells avoid their recognition and destruction by HIF-1. Tumor immune evasion allows cancer cells to proliferate and metastasize and is associated with immunotherapy failure and chemoresistance. In the hypoxic tumor microenvironment, HIF-1 signaling suppresses the innate and adaptive immune systems to evade immune attack by inducing the expression of immunosuppressive factors and immune checkpoint molecules, including vascular endothelial growth factor, prostaglandin E2 , and programmed death-ligand 1/programmed death-1. Moreover, HIF-1 blocks tumor-associated antigen presentation via major histocompatibility complex class I chain-related/natural killer group 2, member D signaling. Tumor-associated autophagy and the release of tumor-derived exosomes contribute to HIF-1-mediated immune evasion. This review focuses on recent findings on the potential mechanism(s) underlying the effect of hypoxia and HIF-1 signaling on tumor immune evasion in the hypoxic tumor microenvironment. The effects of HIF-1 on immune checkpoint molecules, immunosuppressive molecules, autophagy, and exosomes have been described. Additionally, the potential role of HIF-1 in the regulation of tumor-derived exosomes, as well as the roles of HIF-1 and exosomes in tumor evasion, are discussed. This study will contribute to our understanding of HIF-1-mediated tumor immune evasion, leading to the development of effective HIF-1-targeting drugs and immunotherapies.

• MeSH
• faktor 1 indukovatelný hypoxií * MeSH
• hypoxie MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• únik nádoru z imunitní kontroly * MeSH
• vaskulární endoteliální růstový faktor A MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The underlying mechanism of tumor immune evasion is a highly concerning subject for researchers. Increasing evidences reveal that the over-activated signal transducer and activator of transcription 3 (STAT3) is a crucial molecular hub in malignant tumors. STAT3 controls autophagy molecules that impair CTL-mediated tumor cell lysis, inhibiting natural killer cells and inducing apoptosis in T lymphocytes to create an immunosuppressive environment. STAT3 signaling regulates the expression of immune factors and recruits immunosuppressive cells to establish a tolerant tumor microenvironment (TME). STAT3 signaling regulates the expression of immune factors and recruits immunosuppressive cells to create an immunosuppressive environment. All this aid tumor cells in escaping from immune surveillance. In this review, we outlined the STAT3-mediated mechanisms involved in tumor immune evasion and their potential regulatory functions in the TME. We discussed the impact of STAT3 signaling on PD-L1, HIF-1α, exosome, lncRNA, and autophagy in the promotion of tumor immune evasion and highlighted the recent research on STAT3 signaling and tumor immune evasion that may assist in developing effective STAT3-targeted drugs for advancing immunotherapy.

• MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí MeSH
• signální transdukce MeSH
• transkripční faktor STAT3 * metabolismus   MeSH
• únik nádoru z imunitní kontroly * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Days ago, the Nobel Prize in Physiology or Medicine 2018 was awarded jointly to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation". This news has increased the attention on immunotoxicity and immune evasion mechanisms, which are once again hot research topics. Actually, increasing lines of evidence show that trichothecene mycotoxins have a strong immunosuppressive effect. These mycotoxins suppress the host immunity and make them more sensitive to the infection of pathogens, including bacteria and viruses. However, the underlying mechanism(s) in this context is still poorly understood. Interestingly, recent work showed that an immune evasion mechanism might be involved in trichothecene immunotoxicity. In this work, we discuss the potential immune evasion mechanism in trichothecene immunotoxicity. More importantly, under these circumstances, we are pleased to compile a Special Issue entitled "Biochemistry, Molecular Biology, and Toxicology of Natural and Synthetic Toxins" for the International Journal of Molecular Sciences (IJMS). Researchers are encouraged to share their latest interesting findings with the readers of IJMS.

• MeSH
• imunitní únik * MeSH
• imunosupresiva farmakologie   terapeutické užití   MeSH
• lidé MeSH
• trichotheceny farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• úvodní články MeSH
• úvodníky MeSH

CD58 is an adhesion molecule that is known to play a critical role in costimulation of effector cells and is intrinsic to immune synapse structure. Herein, we describe a virally encoded gene that inhibits CD58 surface expression. Human cytomegalovirus (HCMV) UL148 was necessary and sufficient to promote intracellular retention of CD58 during HCMV infection. Blocking studies with antagonistic anti-CD58 mAb and an HCMV UL148 deletion mutant (HCMV∆UL148) with restored CD58 expression demonstrated that the CD2/CD58 axis was essential for the recognition of HCMV-infected targets by CD8+ HCMV-specific cytotoxic T lymphocytes (CTLs). Further, challenge of peripheral blood mononuclear cells ex vivo with HCMV∆UL148 increased both CTL and natural killer (NK) cell degranulation against HCMV-infected cells, including NK-driven antibody-dependent cellular cytotoxicity, showing that UL148 is a modulator of the function of multiple effector cell subsets. Our data stress the effect of HCMV immune evasion functions on shaping the immune response, highlighting the capacity for their potential use in modulating immunity during the development of anti-HCMV vaccines and HCMV-based vaccine vectors.

• MeSH
• buněčná imunita * MeSH
• buňky NK imunologie   patologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   patologie   MeSH
• cytomegalovirové infekce genetika   imunologie   patologie   MeSH
• Cytomegalovirus genetika   imunologie   MeSH
• imunitní únik * MeSH
• lidé MeSH
• proteiny virové fúze genetika   imunologie   MeSH
• transformované buněčné linie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

T-2 toxin and deoxynivalenol (DON) are type A and B trichothecenes, respectively. They widely occur as pollutants in food and crops and cause a series of toxicities, including immunotoxicity, hepatotoxicity, and neurotoxicity. Oxidative stress is the primary mechanistic basis of these toxic effects. Increasing amounts of evidence have shown that mitochondria are significant targets of apoptosis caused by T-2 toxin- and DON-induced oxidative stress via regulation of Bax/B-cell lymphoma-2 and caspase-3/caspase-9 signaling. DNA methylation and autophagy are involved in oxidative stress related to apoptosis, and hypoxia and immune evasion are related to oxidative stress in this context. Hypoxia induces oxidative stress by stimulating mitochondrial reactive oxygen species production and regulates the expression of cytokines, such as interleukin-1β and tumor necrosis factor-α. Programmed cell death-ligand 1 is upregulated by these cytokines and by hypoxia-inducible factor-1, which allows it to bind to programmed cell death-1 to enable escape of immune cell surveillance and achievement of immune evasion. This review concentrates on novel findings regarding the oxidative stress mechanisms of the trichothecenes T-2 toxin and DON. Importantly, we discuss the new evidence regarding the connection of hypoxia and immune evasion with oxidative stress in this context. Finally, the trinity of hypoxia, oxidative stress and immune evasion is highlighted. This work will be conducive to an improved understanding of the oxidative stress caused by trichothecene mycotoxins.

• MeSH
• apoptóza účinky léků   MeSH
• hypoxie chemicky indukované   MeSH
• imunitní únik účinky léků   MeSH
• lidé MeSH
• mitochondrie účinky léků   patologie   MeSH
• oxidační stres účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• T-2 toxin toxicita   MeSH
• trichotheceny toxicita   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Trichothecene mycotoxin deoxynivalenol (DON) negatively regulates immune response by damaging host immune system and harming the organism's health. We hypothesized that DON can initiate an active immunosuppressive mechanism similar to "immune evasion" to alter the cellular microenvironment and evade immune surveillance. We tested this hypothesis using the RAW264.7 macrophage model. DON rapidly increased the expression of immune checkpoints PD-1 and PD-L1, inflammatory cytokine TGF-β, and key immune evasion factors STAT3, VEGF, and TLR-4, and caused cellular hypoxia. Importantly, hypoxia-inducible factor-1α (HIF-1α) acts as a key regulator of DON-induced immunosuppression. HIF-1α accumulated in the cytoplasm and was gradually transferred to the nucleus following DON treatment. Moreover, DON activated HIF-1α through STAT3 signaling to upregulate downstream signaling, including PD-1/PD-L1. Under DON treatment, immunosuppressive miR-210-3p, lncRNA PVT1, lncRNA H19, and lncRNA HOTAIR were upregulated by the STAT3/HIF-1α axis. Moreover, DON damaged mitochondrial function, causing mitophagy, and suppressed immune defenses. Collectively, DON triggered RAW264.7 intracellular hypoxia and rapidly activated HIF-1α via STAT3 signaling, activating immune evasion signals, miRNAs, and lncRNAs, thereby initiating the key link of immune evasion. This study offers further clues for accurate prevention and treatment of immune diseases caused by mycotoxins.

• MeSH
• antigeny CD274 * metabolismus   MeSH
• antigeny CD279 MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• imunita MeSH
• nádorové buněčné linie MeSH
• RNA dlouhá nekódující * MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH

V této práci jsou shrnuty recentní poznatky o mechanismech zahájení imunitní odpovědi. Dále diskutujeme důkazy o tom, že imunitní systém je schopen kontrolovat a regulovat růst nádorových buněk, zejména v raných stadiích karcinogeneze. Výsledky ze studií na lidských modelech také potvrzují, že imunitní systém účinně potlačuje nádorové onemocnění v časných fázích, ve stadiu preneoplazie a při úniku nádorových buněk imunitnímu dohledu je již imunitní reakce méně účinná. Tyto nálezy podporují ideu, že pokusy o aplikaci protinádorové imunoterapie v praxi mají největší naději na úspěch, jestliže bude imunoterapie aplikována v časných fázích onemocnění, nejlépe ve stadiu preneoplazie. Lze dokonce uvažovat o protinádorové imunoterapii u pacientů s vysokým rizikem vzniku nádoru dokonce ještě před rozvojem onemocnění – jako imunoprevenci. Očkování proti virům, které způsobují nádorová onemocnění, jasně ukazuje, že imunoprevence může vést k zásadnímu snížení počtu nádorových onemocnění.

In this review, we first summarize current knowledge about the initiation of the immune response. We then discuss recent findings on the role of immune system in protection from cancer. We discuss the current understanding of the interactions between tumours and cells of the immune system particularly at the early stages of carcinogenesis. A growing body of data suggests that these interactions help sculpt the eventual development of tumours. Recent data from human and mice studies clearly show that the immune system is capable of detecting and eliminating the smallest expansions of transformed cells, well before the development of clinical cancer. These advances suggest a need to change the current emphasis for harnessing anti-tumor immunity from therapy of advanced disease to the immunotherapy of early lesions preferably even to the prevention of cancers.

• MeSH
• aktivace lymfocytů MeSH
• buněčná imunita MeSH
• cytokiny MeSH
• dendritické buňky MeSH
• financování organizované MeSH
• imunitní dozor MeSH
• imunoterapie MeSH
• lidé MeSH
• nádory imunologie   MeSH
• receptory imunologické MeSH
• toll-like receptory MeSH
• tvorba protilátek MeSH
• únik nádoru z imunitní kontroly MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Trichothecene mycotoxins have a strong immunosuppressive effect, which may even escape host immune surveillance and damage the immune repair to show an "immune evasion" effect. Increasing lines of evidence have shown that hypoxia and hypoxia-inducible factors (HIFs) are key mediators of trichothecenes, and these toxins appear to be closely related to the "immune evasion" mechanisms. Therefore, we used RAW264.7 cell model to explore the association of T-2 toxins with "immune evasion" process and hypoxia, as well as their cross-linking effects induced by T-2 toxin. Our results showed that HIF-1α is an important toxicity target of T-2 toxin, which could induce intracellular hypoxia. T-2 toxin induced an "immune evasion" process by activating the PD-1/PD-L1 signaling pathway. Interestingly, when HIF-1α activation was blocked, the "immune evasion" process regulated by PD-1/PD-L1 signaling was activated, resulting in the cells damage, suggesting that hypoxia induced by T-2 toxin plays a protective role for RAW264.7 cell damage. Thus, our work shows that HIF-1α inhibits T-2 toxin-mediated "immune evasion" process by negatively regulating PD-1/PD-L1signaling. This study contributes to a better understanding of the immunotoxicity mechanism of trichothecenes.

• MeSH
• antigeny CD274 metabolismus   MeSH
• antigeny CD279 metabolismus   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa farmakologie   MeSH
• hypoxie MeSH
• lidé MeSH
• T-2 toxin * toxicita   MeSH
• trichotheceny * toxicita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Publikační typ
• abstrakt z konference MeSH

Myxozoans are microscopic, metazoan, obligate parasites, belonging to the phylum Cnidaria. In contrast to the free-living lifestyle of most members of this taxon, myxozoans have complex life cycles alternating between vertebrate and invertebrate hosts. Vertebrate hosts are primarily fish, although they are also reported from amphibians, reptiles, trematodes, mollusks, birds and mammals. Invertebrate hosts include annelids and bryozoans. Most myxozoans are not overtly pathogenic to fish hosts, but some are responsible for severe economic losses in fisheries and aquaculture. In both scenarios, the interaction between the parasite and the host immune system is key to explain such different outcomes of this relationship. Innate immune responses contribute to the resistance of certain fish strains and species, and the absence or low levels of some innate and regulatory factors explain the high pathogenicity of some infections. In many cases, immune evasion explains the absence of a host response and allows the parasite to proliferate covertly during the first stages of the infection. In some infections, the lack of an appropriate regulatory response results in an excessive inflammatory response, causing immunopathological consequences that are worse than inflicted by the parasite itself. This review will update the available information about the immune responses against Myxozoa, with special focus on T and B lymphocyte and immunoglobulin responses, how these immune effectors are modulated by different biotic and abiotic factors, and on the mechanisms of immune evasion targeting specific immune effectors. The current and future design of control strategies for myxozoan diseases is based on understanding this myxozoan-fish interaction, and immune-based strategies such as improvement of innate and specific factors through diets and additives, host genetic selection, passive immunization and vaccination, are starting to be considered.

• MeSH
• adaptivní imunita * MeSH
• antiparazitární látky farmakologie   MeSH
• B-lymfocyty imunologie   metabolismus   parazitologie   MeSH
• imunitní únik MeSH
• imunoglobuliny imunologie   metabolismus   MeSH
• interakce hostitele a parazita MeSH
• Myxozoa účinky léků   imunologie   patogenita   MeSH
• nemoci ryb imunologie   metabolismus   parazitologie   prevence a kontrola   MeSH
• parazitární nemoci u zvířat imunologie   metabolismus   parazitologie   prevence a kontrola   MeSH
• přirozená imunita * MeSH
• ryby imunologie   metabolismus   parazitologie   MeSH
• T-lymfocyty imunologie   metabolismus   parazitologie   MeSH
• vakcíny farmakologie   MeSH
• vodní hospodářství MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH