Východiska: Pro správnou funkci imunitního systému je důležitá souhra mezi inhibičními a stimulačními mechanizmy, které jednak chrání organizmus před cizorodými mikroorganizmy a látkami z vnějšího prostředí, ale také brání zdravou tkáň před případnými poškozujícími útoky imunitního systému. Inhibiční mechanizmy jsou tedy nepostradatelnou složkou imunitního systému podílející se na jeho správné funkci. Nádorové buňky však mohou inhibiční mechanizmy zneužít k úniku před imunitní reakcí a tím podpořit vznik a rozvoj nádorového onemocnění. Proto je tedy za jednu z charakteristik nádorových buněk považovaná schopnost vyhnout se imunitnímu dozoru. Imunoterapie je léčebným postupem, v průběhu kterého dochází ke stimulaci imunitního systému. Za efektivní a specifické imunoterapeutické cíle jsou považovány kontrolní body imunitní reakce. V posledních letech je značná pozornost věnována inhibiční dráze PD-1/PD-L1, tj. dráze programované buněčné smrti. Blokádou PD-1/PD-L1 dochází k utlumení inhibičního signálu, k obnovení účinnosti imunitních mechanizmů a ke zvýšení protinádorové aktivity. Protilátky blokující receptor PD-1 a jeho ligand PD-L1 jsou již poměrně úspěšně klinicky využívány. Přesto je stále velmi důležité vést výzkum se zaměřením na objasnění mechanizmu této dráhy, na nalezení faktorů významně ovlivňujících její aktivitu a na popis variability této dráhy vycházející z různorodosti nádorového prostředí. Získané výsledky lze poté využít k dosažení maximálního protinádorového účinku inhibicí osy PD-1/PD-L1. Cíl: Cílem tohoto článku je shrnout dosavadní poznatky o PD-1/PD-L1 signální dráze a prodiskutovat její úlohu v protinádorové imunitní odpovědi.

Background: Correct function of the immune system depends on close cooperation between stimulation and inhibition signals, which protect an organism from outside microorganisms and other agents, but also protects healthy tissues against possible self-destructing attacks of the immune system. However, the inhibitory mechanisms can be abused by cancer cells that evade immune responses and, in fact, they help develop cancer. Therefore, one of the characteristics of cancer cells is the ability to evade immune recognition. Immunotherapy is a treatment method that stimulates the immune system to fight cancer. The checkpoints of the immune system can be considered as effective and specific therapeutic targets. Programmed cell death signaling pathway (PD-1/PD-L1) is one of the most discussed inhibition pathways in recent years. Blockage of PD-1/PD-L1 interaction restores mechanisms of immune response and increases antitumor immune activity. Monoclonal antibodies blocking PD-1 receptor or its ligand PD-L1 have already shown clinical efficacy. However, it is important to carry out research to explore the mechanisms of PD-1/PD-L1 pathway to find new factors, which influence its activity and, of course, to illuminate the variability of this pathway which naturally originates in the diversity of the tumor milieu. Obtained results could be utilized to achieve maximal anticancer effect after inhibition of PD-1/PD-L1 signaling pathway useful in clinical practice. Aim: The aim of the article is to summarize current knowledge about PD-1/PD-L1 signaling pathway and to discuss its role in antitumor immune response.

• MeSH
• antigeny CD274 * antagonisté a inhibitory   fyziologie   MeSH
• antigeny CD279 * antagonisté a inhibitory   fyziologie   MeSH
• buněčná smrt MeSH
• imunitní systém - jevy fyziologie   MeSH
• lidé MeSH
• nádory patologie   MeSH
• protinádorové látky klasifikace   terapeutické užití   MeSH
• regulace genové exprese u nádorů fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Následující kazuistika pojednává o přínosech a potenciálních rizicích jedné z nejmodernějších léčebných modalit, které v klinické onkologii máme k dispozici. Imunoterapie cílená na kontrolní body imunitní reakce dokáže zejména ve dvojkombinaci dosáhnout významné a trvalé léčebné odpovědi u poměrně vysokého procenta pacientů. Tyto impozantní terapeutické výsledky však nejsou bez nežádoucích účinků. Rizikovější stran vývoje toxicity a dávkově dependentní je použití molekuly cílící na receptor CTLA-4. Méně případů autoimunitních reakcí potom pozorujeme při použití anti-PD-1 monoklonálních protilátek, a ještě méně při užití anti-PD-LI monoklonálních protilátek. Jak víme již z mnoha klinických studií, autoimunitně podmíněné nežádoucí účinky imunoterapie jsou většinou spojeny i s léčebným efektem. Přesně tento kauzální důkaz nám bude demonstrovat náš kazuistický případ.

The following case report discusses the benefits and potential risks of one of the most modern treatment modalities available to us in clinical oncology. Immunotherapy targeted at control points of the immune response can achieve a significant and lasting therapeutic response in a relatively high percentage of patients, especially in a double combination. However, these impressive therapeutic results are not without side effects. The use of a molecule targeting the CTLA-4 receptor is riskier for the development of toxicity and is dose-dependent. Fewer cases of autoimmune reactions are then observed with the use of anti-PD-1 monoclonal antibodies and even less with the use of anti-PD-LI monoclonal antibodies. As we already know from many clinical studies, autoimmune-related adverse effects of immunotherapy are mostly associated with the therapeutic effect. The following case study shows exactly this causal evidence.

• MeSH
• bronchogenní karcinom * diagnóza   farmakoterapie   klasifikace   MeSH
• farmakologické účinky - molekulární mechanismy MeSH
• imunoterapie metody   MeSH
• inhibitory kontrolních bodů * farmakologie   klasifikace   terapeutické užití   MeSH
• ipilimumab farmakologie   terapeutické užití   MeSH
• karboplatina farmakologie   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• nežádoucí účinky léčiv klasifikace   MeSH
• nivolumab farmakologie   terapeutické užití   MeSH
• paclitaxel farmakologie   terapeutické užití   MeSH
• počítačová rentgenová tomografie metody   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• kazuistiky MeSH

INTRODUCTION: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many malignancies in recent years. However, immune-related adverse events (irAE) are a frequent concern in clinical practice. The safety profile of ICI for the treatment of malignancies in patients diagnosed with autoimmune and cholestatic liver disease (AILD) remains unclear. Due to this uncertainty, these patients were excluded from ICI clinical trials and ICI are withheld from this patient group. In this retrospective multicenter study, we assessed the safety of ICI in patients with AILD. METHODS: We contacted tertiary referral hospitals for the identification of AILD patients under ICI treatment in Europe via the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Fourteen centers contributed data on AILD patients with malignancies being treated with ICI, another three centers did not treat these patients with ICI due to fear of irAEs. RESULTS: In this study, 22 AILD patients under ICI treatment could be identified. Among these patients, 12 had primary biliary cholangitis (PBC), five had primary sclerosing cholangitis (PSC), four had autoimmune hepatitis (AIH), and one patient had an AIH-PSC variant syndrome. Eleven patients had hepatobiliary cancers and the other 11 patients presented with non-hepatic tumors. The applied ICIs were atezolizumab (n=7), durvalumab (n=5), pembrolizumab (n=4), nivolumab (n=4), spartalizumab (n=1), and in one case combined immunotherapy with nivolumab plus ipilimumab. Among eight patients who presented with grade 1 or 2 irAEs, three demonstrated liver irAEs. Cases with grades ≥ 3 irAEs were not reported. No significant changes in liver tests were observed during the first year after the start of ICI. DISCUSSION: This European multicenter study demonstrates that PD-1/PD-L1 inhibitors appear to be safe in patients with AILD. Further studies on the safety of more potent dual immune checkpoint therapy are needed. We conclude that immunotherapy should not categorically be withheld from patients with AILD.

• MeSH
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• autoimunitní hepatitida * farmakoterapie   MeSH
• cholestáza * MeSH
• inhibitory kontrolních bodů škodlivé účinky   MeSH
• lidé MeSH
• nádory * MeSH
• nivolumab škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

Cell surface expression of PD-1, PD-L1 and PD-L2 immune checkpoints on B and T cells obtained from patients with mantle cell lymphoma shows ambiguous results across many studies and creates obstacles for the implementation of immune checkpoint inhibitors into the therapy of mantle cell lymphoma. Using multiparameter flow cytometry we analysed surface expression of PD-1, PD-L1 and PD-L2 molecules on B and T cells of 31 newly diagnosed mantle cell lymphomas and compared it with the results of 26 newly diagnosed chronic lymphocytic leukaemias and 20 healthy volunteers. To gain insight into the age-dependent changes of surface expression of these immune checkpoints, flow cytometric subanalysis of 30 healthy volunteers of 25-93 years of age was conducted. Overall, we demonstrated weak surface expression of PD-1, PD-L1 and PD-L2 on B and T cells of mantle cell lymphoma patients (< 10 % when compared to healthy individuals). A significant age-dependent increase in the expression of PD-1 and its ligand PD-L2 was observed in healthy volunteers. Our results suggest that neither PD-1 nor its ligands represent relevant druggable targets for the therapy of mantle cell lymphoma. The observed age-dependent changes in healthy population could impact efficiency of immune checkpoint inhibitors and could be at least partly connected with increased incidence of cancer with age.

• MeSH
• antigeny CD273 metabolismus   MeSH
• antigeny CD274 metabolismus   MeSH
• antigeny CD279 metabolismus   MeSH
• B-lymfocyty MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfom z plášťových buněk metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• T-lymfocyty MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

The introduction of PD-1/PD-L1 pathway inhibitors is an important landmark in solid oncology with unprecedented practice-changing activity in various types of solid tumours. Among haematological malignancies, PD-1/PD-L1 inhibitors have been successful, so far, only in the treatment of classical Hodgkin lymphoma, which typically exhibits an over-expression of PD-1 ligands (PD-L1, PD-L2) due to alterations in chromosome 9p24.1. Such positive outcomes led to the US Food and Drug Administration approval of nivolumab use in relapsed Hodgkin lymphoma in 2016 as the first haematological indication. Although the results in other lymphoid malignancies have not been so striking, blockade of the PD-1/PD-L1 axis has led to meaningful responses in other lymphoma types such as diffuse large B-cell lymphoma, follicular lymphoma or several T-cell lymphomas. Monotherapy with PD-1/PD-L1 inhibitors in chronic lymphocytic leukaemia and multiple myeloma has been unsatisfactory, suggesting that a combinational approach with other synergistic drugs is needed. In the case of multiple myeloma, immunomodulatory agents together with corticosteroids represent the most promising combinations. Among myeloid malignancies, the anti-PD-1 monoclonal antibodies are examined dominantly in acute myeloid leukaemia and myelodysplastic syndromes in combination with potentially synergistic hypomethylating drugs such as 5-azacitidine, resulting in promising outcomes that warrant further investigation. We have described all available clinical results of PD-1/PD-L1 inhibitors in haematological malignancies and discussed related toxicities, as well as highlighted crucial preclinical studies in this review.

• MeSH
• antigeny CD274 antagonisté a inhibitory   imunologie   metabolismus   MeSH
• antigeny CD279 antagonisté a inhibitory   imunologie   metabolismus   MeSH
• cílená molekulární terapie MeSH
• hematologické nádory farmakoterapie   imunologie   metabolismus   patologie   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• medicína založená na důkazech MeSH
• protinádorové látky škodlivé účinky   terapeutické užití   MeSH
• signální transdukce účinky léků   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and aggressive tumor affecting mostly younger patients. This is the first study to assess the expression of programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) in FH-RCC. Formalin-fixed paraffin-embedded samples from 13 FH-RCCs collected in an international multi-institutional study, were evaluated by immunohistochemistry (IHC) for PD-1/PD-L1 reactivity in tumor cells and tumor infiltrating lymphocytes (TILs). PD-1/PD-L1 expression was further evaluated by qPCR. By IHC, PD-1 was negative in tumor cells in all 13 cases. PD-L1 was positive in tumor cells in 2/13 cases, weak positive in 7/13, and negative in 4/13 cases, respectively. In TILs, PD-1 was positive in 1/13, weak positive in 3/13, and negative in 9/13 cases. In TILs, PD-L1 was weak positive by IHC in 5/13, and negative in 8/13 cases, respectively. qPCR confirmed the result for 2 of 3 IHC weak positive PD-1 samples. Of 7 IHC weak positive samples (in tumor cells), PD-L1 mRNA was detected in all 7 tumors. The majority of FH-RCCs did not express PD-1/PD-L1 by IHC, which was confirmed by molecular analysis. PD-1/PD-L1 expression in FH-RCC is restricted to a proportion of cases which may benefit from targeted therapies.

• MeSH
• antigeny CD274 metabolismus   MeSH
• antigeny CD279 metabolismus   MeSH
• dospělí MeSH
• fumarasa nedostatek   metabolismus   MeSH
• imunohistochemie metody   MeSH
• karcinom z renálních buněk metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory ledvin metabolismus   patologie   MeSH
• přežití bez známek nemoci MeSH
• tumor infiltrující lymfocyty metabolismus   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade is a promising therapy for various cancer types, but most patients are still resistant. Therefore, a larger number of predictive biomarkers is necessary. In this study, we assessed whether a loss-of-function mutation of the interferon (IFN)-γ receptor 1 (IFNGR1) in tumor cells can interfere with anti-PD-L1 therapy. For this purpose, we used the mouse oncogenic TC-1 cell line expressing PD-L1 and major histocompatibility complex class I (MHC-I) molecules and its TC-1/A9 clone with reversibly downregulated PD-L1 and MHC-I expression. Using the CRISPR/Cas9 system, we generated cells with deactivated IFNGR1 (TC-1/dIfngr1 and TC-1/A9/dIfngr1). In tumors, IFNGR1 deactivation did not lead to PD-L1 or MHC-I reduction on tumor cells. From potential inducers, mainly IFN-α and IFN-β enhanced PD-L1 and MHC-I expression on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vitro. Neutralization of the IFN-α/IFN-β receptor confirmed the effect of these cytokines in vivo. Combined immunotherapy with PD-L1 blockade and DNA vaccination showed that IFNGR1 deactivation did not reduce tumor sensitivity to anti-PD-L1. Thus, the impairment of IFN-γ signaling may not be sufficient for PD-L1 and MHC-I reduction on tumor cells and resistance to PD-L1 blockade, and thus should not be used as a single predictive marker for anti-PD-1/PD-L1 cancer therapy.

• MeSH
• antigeny CD274 antagonisté a inhibitory   MeSH
• antigeny CD279 antagonisté a inhibitory   MeSH
• experimentální nádory farmakoterapie   imunologie   metabolismus   patologie   MeSH
• imunoterapie MeSH
• interferon gama antagonisté a inhibitory   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• protinádorové látky imunologicky aktivní farmakologie   MeSH
• transformované buněčné linie účinky léků   imunologie   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The therapy of different advanced-stage malignancies with monoclonal antibodies blocking programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling has had an impressive long-lasting effect in a portion of patients, but in most cases, this therapy was not successful, or a secondary resistance developed. To enhance its efficacy in treated patients, predictive biomarkers are searched for and various combination treatments are intensively investigated. As the downregulation of major histocompatibility complex (MHC) class I molecules is one of the most frequent mechanisms of tumor escape from the host's immunity, it should be considered in PD-1/PD-L1 checkpoint inhibition. The potential for the use of a PD-1/PD-L1 blockade in the treatment of tumors with aberrant MHC class I expression is discussed, and some strategies of combination therapy are suggested.

• MeSH
• antigeny CD274 antagonisté a inhibitory   imunologie   MeSH
• antigeny CD279 antagonisté a inhibitory   imunologie   MeSH
• down regulace * MeSH
• geny MHC třídy I MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• MHC antigeny I. třídy genetika   MeSH
• monoklonální protilátky terapeutické užití   MeSH
• nádory genetika   imunologie   terapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• Klíčová slova
• imunitní kontrolní bod, adaptivní rezistence,
• MeSH
• antigeny CD273 imunologie   MeSH
• antigeny CD274 * imunologie   MeSH
• antigeny CD279 * imunologie   MeSH
• imunitní systém - jevy MeSH
• imunomodulace MeSH
• imunoterapie MeSH
• lidé MeSH
• nádorové mikroprostředí imunologie   MeSH
• nádory * imunologie   MeSH
• únik nádoru z imunitní kontroly MeSH
• Check Tag
• lidé 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