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.

• Klíčová slova
• Fumarate hydratase-deficient renal cell carcinoma, Kidney, PD-1 ligand (PD-L1) receptor, Programmed death-1 (PD-1) receptor,
• 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 po terapii bez příznaků 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
• Názvy látek
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• CD274 protein, human MeSH Prohlížeč
• fumarasa MeSH
• PDCD1 protein, human MeSH Prohlížeč

BACKGROUND: The programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) pathway is important in metastatic renal cell carcinoma (mRCC). However, some dissimilarities between anti-PD-1 and anti-PD-L1 inhibitors have emerged. We aimed to assess differences between anti-PD-1 and anti-PD-L1 combination immunotherapies as first-line treatments in mRCC patients. METHODS: Multiple databases (PubMed, Web of Science, and Scopus) were searched for articles published until March 2021. Studies were eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORR), complete response rates (CRR), and adverse events. RESULTS: Five studies met the eligibility criteria. PD-1 combination therapy was associated with significantly better OS and PFS and higher ORR and CRR than sunitinib (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.40-0.89; HR: 0.52, 95% CI: 0.37-0.75; odds ratio [OR]: 3.20, 95% CI: 2.18-4.68; and OR: 3.05, 95% CI: 2.13-4.37, respectively; P < 0.001). For all oncological outcomes, anti-PD-1 agents were superior to anti-PD-L1 agents based on HR and OR (OS: HR = 0.88, PFS: HR = 0.76, ORR: OR = 1.85, and CRR: OR = 2.24). Conversely, anti-PD-L1 agents were superior to anti-PD-1 agents in their safety profiles. In network meta-analyses, pembrolizumab plus lenvatinib seemed the worst tolerated anti-PD-1 combination therapy. CONCLUSIONS: Our analysis indicates the superior oncologic benefits of first-line anti-PD-1 combination therapies over anti-PD-L1 combination therapies in mRCC patients. This biological difference is of vital importance for clinical treatment decision making and the design of future rational combination therapy trials in mRCC.

• Klíčová slova
• Combination therapy, Meta-analysis, Metastatic renal cell carcinoma, Programmed cell death-1 inhibitors, Programmed cell death-ligand 1 inhibitors,
• MeSH
• antigeny CD274 antagonisté a inhibitory   imunologie   MeSH
• antigeny CD279 antagonisté a inhibitory   imunologie   MeSH
• inhibitory kontrolních bodů aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• karcinom z renálních buněk farmakoterapie   imunologie   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• nádory ledvin farmakoterapie   imunologie   MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH
• Názvy látek
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• CD274 protein, human MeSH Prohlížeč
• inhibitory kontrolních bodů MeSH
• PDCD1 protein, human MeSH Prohlížeč

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.Key words: programmed cell death pathway - tumor escape - PD-1 - PD-L1 - CD274This work was supported by the project MEYS - NPS I - LO1413.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 13. 6. 2016Accepted: 4. 8. 2016.

• MeSH
• antigeny CD274 antagonisté a inhibitory   metabolismus   MeSH
• antigeny CD279 antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• nádory farmakoterapie   imunologie   metabolismus   MeSH
• signální transdukce MeSH
• únik nádoru z imunitní kontroly imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• CD274 protein, human MeSH Prohlížeč
• PDCD1 protein, human MeSH Prohlížeč

The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds are emerging as an attractive alternative that can potentially overcome the drawbacks of mAb-based therapy. In this article, we present a novel class of small molecule compounds based on the terphenyl scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an m-terphenyl core, an additional aromatic ring, and a solubilizing agent. Using molecular docking, we designed a series of final compounds, which were subsequently synthesized and tested in HTRF assay and NMR binding assay to evaluate their activity. In addition, we performed an in-depth analysis of the mutual arrangement of the phenyl rings of the terphenyl core within the binding pocket of PD-L1 and found several correlations between the plane angle values and the affinity of the compounds towards the protein.

• Klíčová slova
• C2-symmetrical ligands, PD-L1, cancer, immune checkpoint, small molecule inhibitor,
• MeSH
• antigeny CD274 * antagonisté a inhibitory   metabolismus   chemie   MeSH
• antigeny CD279 * antagonisté a inhibitory   metabolismus   chemie   MeSH
• inhibitory kontrolních bodů chemie   farmakologie   MeSH
• knihovny malých molekul farmakologie   chemie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• simulace molekulového dockingu * MeSH
• terfenylové sloučeniny * chemie   farmakologie   MeSH
• vazba proteinů * MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD274 * MeSH
• antigeny CD279 * MeSH
• CD274 protein, human MeSH Prohlížeč
• inhibitory kontrolních bodů MeSH
• knihovny malých molekul MeSH
• PDCD1 protein, human MeSH Prohlížeč
• terfenylové sloučeniny * MeSH

PURPOSE: To detect the expression of programmed death-ligand 1 (PD-L1) in Merkel cell carcinoma (MCC) and to determine the prognostic influence of the PD-L1 expression. METHODS: A total of 13 patients with MCC were retrospectively evaluated (12 patients with primary skin lesion, one patient was diagnosed as unknown primary MCC). All patients underwent surgical resection. PD-L1 was determinated by imunohistochemistry. Immunostaining results were evaluated semiquantitatively. The prognostic influence of the expression of PD-L1 on overall survival (OS) was calculated with the Kaplan-Meier method and log-rank test. RESULTS: PD-L1 positivity was detected in 8 patients (61.5%), in all cases the result was 1+. PD-L1 negativity was shown in the remaining 5 patients. In patients with PD-L1 positivity median OS was 42.1 months (95% CI 9.3-42.1) compared with median OS of 9.4 months (95% CI 2.1-80.9) in the group of patients without PD-L1 positivity (p=0.417). CONCLUSIONS: PD-L1 positivity was found in 61.5% of patients with MCC. No prognostic significance of PD-L1 expression for OS was demonstrated.

• MeSH
• antigeny CD274 genetika   MeSH
• dospělí MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• Merkelův nádor diagnóza   diagnostické zobrazování   genetika   patologie   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• prognóza * MeSH
• regulace genové exprese u nádorů genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD274 MeSH
• CD274 protein, human MeSH Prohlížeč

Monoclonal antibodies targeting immune checkpoints have revolutionized oncology. Yet, the effectiveness of these treatments varies significantly among patients, and they are associated with unexpected adverse events, including hyperprogression. The murine research model used in drug development fails to recapitulate both the functional human immune system and the population heterogeneity. Hence, a novel model is urgently needed to study the consequences of immune checkpoint blockade. Dogs appear to be uniquely suited for this role. Approximately 1 in 4 companion dogs dies from cancer, yet no antibodies are commercially available for use in veterinary oncology. Here we characterize two novel antibodies that bind canine PD-1 with sub-nanomolar affinity as measured by SPR. Both antibodies block the clinically crucial PD-1/PD-L1 interaction in a competitive ELISA assay. Additionally, the antibodies were tested with a broad range of assays including Western Blot, ELISA, flow cytometry, immunofluorescence and immunohistochemistry. The antibodies appear to bind two distinct epitopes as predicted by molecular modeling and peptide phage display. Our study provides new tools for canine oncology research and a potential veterinary therapeutic.

• Klíčová slova
• PD-1, PD-L1, cancer immunotherapy, canine cancer, comparative oncology, immune checkpoint, monoclonal antibody, veterinary oncology,
• MeSH
• antigeny CD274 imunologie   antagonisté a inhibitory   metabolismus   MeSH
• antigeny CD279 * antagonisté a inhibitory   imunologie   MeSH
• epitopy imunologie   MeSH
• inhibitory kontrolních bodů imunologie   farmakologie   MeSH
• lidé MeSH
• monoklonální protilátky * imunologie   MeSH
• nádory imunologie   veterinární   farmakoterapie   MeSH
• nemoci psů imunologie   farmakoterapie   MeSH
• psi * MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi * MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• antigeny CD274 MeSH
• antigeny CD279 * MeSH
• epitopy MeSH
• inhibitory kontrolních bodů MeSH
• monoklonální protilátky * 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.

• Klíčová slova
• PD-1/PD-L1 immune checkpoint inhibitors, autoimmune disease (AID), autoimmune hepatitis (AIH), autoimmune liver diseases (AILD), immune checkpoint inhibitors (ICI), immune related adverse effects (irAEs), primary biliary cholangitis (PBC), primary sclerosing cholangites (PSC),
• 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
• Názvy látek
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• inhibitory kontrolních bodů MeSH
• nivolumab 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
• Názvy látek
• antigeny CD273 MeSH
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• CD274 protein, human MeSH Prohlížeč
• PDCD1 protein, human MeSH Prohlížeč
• PDCD1LG2 protein, human MeSH Prohlížeč

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.

• Klíčová slova
• haematological malignancy, myeloma, nivolumab, pembrolizumab, programmed death 1 receptor,
• MeSH
• antigeny CD274 antagonisté a inhibitory   imunologie   metabolismus   MeSH
• antigeny CD279 antagonisté a inhibitory   imunologie   metabolismus   MeSH
• antitumorózní látky škodlivé účinky   terapeutické užití   MeSH
• cílená molekulární terapie MeSH
• hematologické nádory farmakoterapie   imunologie   metabolismus   patologie   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• medicína založená na důkazech 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
• Názvy látek
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• antitumorózní látky MeSH
• CD274 protein, human MeSH Prohlížeč
• PDCD1 protein, human MeSH Prohlížeč

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.

• Klíčová slova
• HIF-1α, Hypoxia, Immune evasion, PD-1/PD-L1, T-2 toxin,
• 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
• Názvy látek
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• T-2 toxin * MeSH
• trichotheceny * MeSH