Úvod: Vzhľadom k liečbe inhibítormi imunitných strážnych bodov, ktorá zlepšuje prognózu pacientov s pokročilým nemalobunkovým karcinómom pľúc, začína stúpať význam imunohistochemickej analýzy na dôkaz proteínového receptora programovanej smrti a jeho liganda, tzv. PD-L1 proteínu. Materiál a metodika: V našej práci prezentujeme výsledky analýzy imunohistochemickej expresie proteínu PD-L1 s použitím klónu 22C3 (na imunostaineri DAKO Link 48) na nádorových bunkách biopsií 325 pacientov s pľúcnym karcinómom. Hodnotenie expresie pomocou tzv. TPS skóre umožnilo rozdeliť súbor na negatívne prípady (žiadna pozitivita alebo menej ako 1 % pozitívnych buniek nádoru) verzus pozitívne, a to v kategóriách 1-9 %, 10-49 % a ≥ 50 % nádorových buniek. Výsledky: Pri porovnaní klinicko-patologických charakteristík podľa stupňa expresie sme zistili porovnateľnú pozitívnu expresiu u pacientov s adenokarcinómom (47,4 % prípadov) a so skvamocelulárnym karcinómom (44,4 %), pričom expresia sa nelíšila v závislosti od veľkosti vzorky pri delení na tzv. malé verzus veľké biopsie. U pacientov s adenokarcinómom sme pozorovali rozdiely expresie PD-L1 proteínu v podskupinách podľa predominantného histopatologického typu. V prípadoch s prevahou lepidického rastu sa pozitívna expresia vyskytla v 18,8 % prípadov, pri prevahe acinárneho a papilárneho rastu v 40,8 % a pri prevahe mikropapilárneho a solídneho rastu až v 74,1 % prípadov. Rohovatejúce skvamocelulárne karcinómy boli pozitívne v 38,5 % a nerohovatejúce v 53,8 % prípadov. Najčastejšia pozitivita vysokého stupňa bola pozorovaná v podskupine pacientov so sarkomatoidným karcinómom. Diskusia a záver: Imunohistochemicky verifikovaná expresia PD-L1 proteínu sa stala akceptovaným prediktívnym biomarkerom pre imunoterapiu pacientov s NSCLC. Naznačené rozdiely expresie podľa jednotlivých podtypov NSCLC vyžadujú verifikáciu vo väčších súboroch v korelácii s klinickými parametrami ochorenia v zmysle overenia jej použiteľnosti aj ako potenciálneho negatívneho prognostického faktora.
Introduction: Recent studies on check-point inhibitor therapy, which seems to improve the prognosis of patients with advanced non-small cell lung carcinoma increase the importance of immunohistochemical analyses of the programmed-death receptor and of its ligand, PD-L1 protein. Material and methods: In our study we present results of PD-L1 immunohistochemical tumor cell expression in a series of 325 lung carcinoma patients biopsies, using the clone 22C3 (and DAKO Link 48 immunostainer). Evaluation of the expression using tissue proportion scoring system allowed to distinguish negative cases (either 0 % or < 1 % of positive tumor cells) versus positive cases in the categories 1-9 %, 10-49 % and ≥ 50 % of positive tumor cells. Results: In association to histopathologic parameters we observed similar rates of positive expression in patients with adenocarcinoma types (47,8 % of all the cases) as well as with squamous cell carcinomas (44,4 %). Within these histological categories, the rates of positivity were similar also in patients with small versus large (resectional) biopsies. In the biopsies of patients with adenocarcinoma we identified differences in the PD-L1 protein expression associated with its histological subtype. In the cases with predominant lepidic pattern the PD-L1 positivity was present in 18,8 %, with predominant acinar or papillary pattern in 40,8 % and in cases with predominant solid or micropapillary component in 74,1 % of the cases resp. Keratinizing squamous cell carcinomas were positive in 38,5 % and non-keratinizing in 53,8 % of all the cases. The hiqhest incidence of an extensive posivity was observed in sarcomatoid carcinoma type. Discussion and conclusion: Immunohistochemically verified PD-L1 protein expression represents a broadly accepted predictive biomarker for immunotherapy of NSCLC patients. The indicated differences of the expression among various NSCLC types and subtypes require to be verified in larger cohorts of patients in relation with clinical parameters to demonstrate whether it could be plausible to use the PD-L1 expression in a role of a negative prognostic parameter.
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.
- MeSH
- B7-H1 Antigen antagonists & inhibitors immunology MeSH
- Programmed Cell Death 1 Receptor antagonists & inhibitors immunology MeSH
- Immune Checkpoint Inhibitors administration & dosage adverse effects therapeutic use MeSH
- Carcinoma, Renal Cell drug therapy immunology MeSH
- Clinical Trials, Phase III as Topic MeSH
- Humans MeSH
- Kidney Neoplasms drug therapy immunology MeSH
- Antineoplastic Combined Chemotherapy Protocols adverse effects therapeutic use MeSH
- Randomized Controlled Trials as Topic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Systematic Review 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
- B7-H1 Antigen metabolism MeSH
- Programmed Cell Death 1 Receptor metabolism MeSH
- Adult MeSH
- Fumarate Hydratase deficiency metabolism MeSH
- Immunohistochemistry methods MeSH
- Carcinoma, Renal Cell metabolism pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Kidney Neoplasms metabolism pathology MeSH
- Disease-Free Survival MeSH
- Lymphocytes, Tumor-Infiltrating metabolism pathology MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Východiská: Inhibítory imunitných kontrolných bodov (ICI) blokujúce signálnu dráhu proteínu 1 programovanej smrti (PD-1), dramaticky zlepšili prežívanie pacientov s pokročilým nemalobunkovým karcinómom pľúc (NSCLC). Imunohistochemická analýza expresie ligandu 1 programovanej smrti (PD-L1) je toho času najviac využívaným a klinicky validovaným biomarkerom predikujúcim efektívnosť ICI u pacientov s NSCLC, ale sám o sebe predstavuje nedokonalý nástroj. Signálna dráha PD-1 je poprepájaná s početnými celulárnymi ako aj molekulárnymi faktormi prítomnými v nádorovom mikroprostredí (TME) v NSCLC. Celulárne faktory, ktoré sa podieľajú na regulácii expresie PD-L1 v NSCLC sú pripisované aktivite nádor infiltrujúcich lymfocytov a s nádorom asociovanými fibroblastmi. Vnútorné molekulárne faktory, ktoré majú vplyv na úroveň expresie PD-L1 v NSCLC, sú asociované s prítomnosťou onkogénnych driver mutácií v génoch receptora epidermálneho rastového faktora a v homológu virového onkogénu Kirsten rat sarcoma a s translokáciami vedúcimi k prestavbe kinázy anaplastického lymfómu. Okrem toho, na úroveň expresie PD-L1 v NSCLC môže mať vplyv aj stimulácia hypoxických signálnych dráh a aktivácia transformujúceho rastového faktora beta 1. Hlbšie pochopenie zložitých mechanizmov regulujúcich expresiu PD-L1 je nevyhnutné, aby bolo v budúcnosti možné ušiť na mieru terapiu s použitím ICI u pacientov s pokročilým NSCLC. Cieľ: V predkladanom prehľadovom článku prezentujeme súhrn kľúčových faktorov podieľajúcich sa na regulácii expresie PD-L1 v rámci TME v NSCLC, ktoré sú a potenciálne môžu byť využívané za účelom zlepšenia účinnosti imunoterapie, ktorá blokuje signálnu dráhu PD-1.
Background: Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 (PD-1) signaling pathway have dramatically improved the clinical outcomes of oncological patients having advanced non-small cell lung carcinoma (NSCLC). The immunohistochemical analysis of programmed death-ligand 1 (PD-L1) expression remains the most widely used and clinically validated biomarker predicting efficacy of ICI in NSCLC patients, but it represents in isolation an imperfect tool. The PD-1 axis is intricately coupled with numerous cellular and molecular factors within the tumor microenvironment (TME) of NSCLC. Cellular factors implicated in the regulation process of PD-L1 expression in NSCLC are related to the activity of tumor infiltrating lymphocytes and cancer associated fibroblasts. Intrinsic molecular factors which affect the level of PD-L1 expression are associated with the presence of oncogenic driver mutations in the Kirsten rat sarcoma viral oncogene homolog and epidermal growth factor receptor genes and to rearrangements in the anaplastic lymphoma kinase. Furthermore, activation of hypoxic signaling pathways and the transforming growth factor beta 1 axis can have an impact on the level of PD-L1 expression in NSCLC. A deeper understanding of the complex mechanisms regulating PD-L1 expression is necessary to tailor the treatment with ICI in patients with advanced NSCLC. Purpose: In this review, we present an overview of key factors underlying the regulation of PD-L1 expression within the TME of NSCLC, which are, and potentially can be, exploited to improve the outcomes of immunotherapy targeting the PD-1 axis.
- MeSH
- B7-H1 Antigen MeSH
- Programmed Cell Death 1 Receptor MeSH
- Humans MeSH
- Biomarkers, Tumor MeSH
- Lung Neoplasms drug therapy genetics MeSH
- Carcinoma, Non-Small-Cell Lung * drug therapy genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
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.
- MeSH
- B7-H1 Antigen * antagonists & inhibitors metabolism chemistry MeSH
- Programmed Cell Death 1 Receptor * antagonists & inhibitors metabolism chemistry MeSH
- Immune Checkpoint Inhibitors chemistry pharmacology MeSH
- Small Molecule Libraries pharmacology chemistry MeSH
- Humans MeSH
- Molecular Structure MeSH
- Molecular Docking Simulation * MeSH
- Terphenyl Compounds * chemistry pharmacology MeSH
- Protein Binding * MeSH
- Binding Sites MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- MeSH
- CD8-Positive T-Lymphocytes cytology immunology MeSH
- T-Lymphocytes, Cytotoxic * MeSH
- Gene Expression MeSH
- HIV Infections immunology MeSH
- HIV * immunology pathogenicity MeSH
- Immune Checkpoint Inhibitors * analysis MeSH
- Clinical Trials as Topic MeSH
- Humans MeSH
- CD4-CD8 Ratio MeSH
- Flow Cytometry MeSH
- Gene Expression Profiling MeSH
- Check Tag
- Humans MeSH
Rezistence k indukci smrti je jedním z charakteristických znaků nádorové buňky, jež ovlivňuje od počátku jak samotný proces neoplastické transformace, tak i pozdější odpověď na onkologickou léčbu. Cílem tohoto přehledového článku je shrnout recentní informace o programované buněčné smrti zdravých i nádorových buněk a o nových možnostech protinádorové terapie zacílené na tyto signální dráhy. Podrobněji jsou popsány tři hlavní typy: apoptóza, programovaná nekróza a buněčná smrt spojená s autofagií. Především apoptóza hraje významnou roli nejen při neoplastické transformaci buňky, ale i jako jeden z faktorů určujících úspěšnost protinádorové terapie. V textu je podán přehled hlavních signálních drah a molekul podílejících se na regulaci apoptózy ve zdravých buňkách. Většina nádorových buněk nese mutace v proteinech přímo či nepřímo se účastnících indukce a exekuce buněčné smrti, jako jsou proteiny p53, členové rodiny Bcl‑2, proteiny inhibující apoptózu (IAPs), receptory/ligandy smrti a další. U těchto významných regulátorů jsou popsány jejich nejčastější mutace či změny exprese vyskytující se v buňkách konkrétních typů nádorů. Na závěr je podán přehled některých nových léčiv zaměřených na modulaci programované buněčné smrti, jež právě procházejí klinickými zkouškami. Díky intenzivnímu výzkumu je možné stále detailnější porozumění procesům, které v umírající buňce probíhají, a na jejich základě pak lze navrhovat léčiva nové generace, jež v kombinaci s tradiční terapií umožní významné zlepšení odpovědi na protinádorovou terapii.
Resistance to programmed cell death is one of the hallmarks of cancer cells that affects the process of malignant transformation as well as response to cancer therapy. The goal of this review is to summarize recent information about programmed cell death (PCD) in healthy and cancer cells, as well as new perspectives for anticancer treatments targeting these signaling pathways. Three main types of PCD are described in detail: apoptosis, necrosis/necroptosis and cell death associated with autophagy. Among them, apoptosis plays the key role in both malignant transformation and response to therapy. In this review, we describe main signaling pathways and molecules participating in apoptosis regulation in healthy cells. In most cancer cells, mutations or aberrant expression of proteins directly or indirectly involved in induction and execution of cell death can be detected – p53, Bcl‑2 family proteins, inhibitors of apoptosis, death receptors/ligands and other proteins. Mutations or changes in expression of these proteins and their relation to certain types of tumors are described. Finally, we provide a review of recently developed treatments that target and reactivate the machinery of programmed cell death and are currently tested in clinical trials. Key words: programmed cell death – apoptosis – necroptosis – autophagy – caspases – Bcl‑2 This work was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) and by MH CZ – DRO (MMCI, 00209805). 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 “uniform requirements” for biomedical papers. Submitted: 14. 1. 2014 Accepted: 6. 3. 2014
- Keywords
- kaspázy,
- MeSH
- Apoptosis * MeSH
- Autophagy * MeSH
- Inhibitor of Apoptosis Proteins MeSH
- Caspases MeSH
- Humans MeSH
- Cell Transformation, Neoplastic * MeSH
- Neoplasms * drug therapy metabolism MeSH
- Necroptosis MeSH
- Necrosis MeSH
- Antineoplastic Agents pharmacology MeSH
- Proto-Oncogene Proteins c-bcl-2 MeSH
- Signal Transduction drug effects MeSH
- Receptors, TNF-Related Apoptosis-Inducing Ligand MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
BACKGROUND: Immunotherapy and targeted therapy are currently two alternative backbones in the therapy of BRAF-mutated malignant melanoma. However, predictive biomarkers that would help with treatment selection are lacking. METHODS: This retrospective study investigated outcomes of anti-programmed death receptor-1 monotherapy and targeted therapy in the first-line setting in patients with metastatic BRAF-mutated melanoma, focusing on clinical and laboratory parameters associated with treatment outcome. RESULTS: Data from 174 patients were analysed. The median progression-free survival (PFS) was 17.0 months (95% CI; 8-39) and 12.5 months (95% CI; 9-14.2) for immunotherapy and targeted therapy, respectively. The 3-year PFS rate was 39% for immunotherapy and 25% for targeted therapy. The objective response rate was 72% and 51% for targeted therapy and immunotherapy. The median overall (OS) survival for immunotherapy has not been reached and was 23.6 months (95% CI; 16.1-38.2) for targeted therapy, with a 3-year survival rate of 63% and 40%, respectively. In a univariate analysis, age < 70 years, a higher number of metastatic sites, elevated serum LDH and a neutrophil-lymphocyte ratio above the cut-off value were associated with inferior PFS regardless of the therapy received, but only serum LDH level and the presence of lung metastases remained significant predictors of PFS in a multivariate analysis. CONCLUSIONS: Present real-world data document the high effectiveness of immunotherapy and targeted therapy. Although targeted therapy had higher response rates, immunotherapy improved PFS and OS. While the prognostic value of LDH was confirmed, the potential use of blood cell count-derived parameters to predict outcomes needs further investigation.
- MeSH
- Humans MeSH
- Melanoma * drug therapy genetics pathology MeSH
- Skin Neoplasms * drug therapy MeSH
- Proto-Oncogene Proteins B-raf genetics MeSH
- Receptors, Death Domain MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial. Methods HRS cells from archival tumor biopsies were evaluated for 9p24.1 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry. These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade. Results Patients with higher-level 9p24.1 copy gain and increased PD-L1 expression on HRS cells had superior PFS. HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy. In contrast, HRS cell expression of MHC class II was predictive for complete remission. In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS. Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade. In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I.
- MeSH
- B7-H1 Antigen antagonists & inhibitors biosynthesis genetics immunology MeSH
- Programmed Cell Death 1 Receptor antagonists & inhibitors biosynthesis genetics immunology MeSH
- beta 2-Microglobulin biosynthesis genetics immunology MeSH
- Reed-Sternberg Cells drug effects immunology pathology MeSH
- Progression-Free Survival MeSH
- Hodgkin Disease drug therapy genetics immunology pathology MeSH
- Cohort Studies MeSH
- Humans MeSH
- Chromosomes, Human, Pair 9 MeSH
- Histocompatibility Antigens Class II biosynthesis genetics immunology MeSH
- Nivolumab therapeutic use MeSH
- Predictive Value of Tests MeSH
- Antigen Presentation MeSH
- Antineoplastic Agents, Immunological therapeutic use MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
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
- B7-H1 Antigen * antagonists & inhibitors physiology MeSH
- Programmed Cell Death 1 Receptor * antagonists & inhibitors physiology MeSH
- Cell Death MeSH
- Immune System Phenomena physiology MeSH
- Humans MeSH
- Neoplasms pathology MeSH
- Antineoplastic Agents classification therapeutic use MeSH
- Gene Expression Regulation, Neoplastic physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
