المؤلفون: Hyunjee Lee, Sang Eun Yoon, Seok Jin Kim, Won Seog Kim, Junhun Cho

المصدر: Cancer Medicine, Vol 12, Iss 15, Pp 16359-16369 (2023)

مصطلحات موضوعية: CD274, diffuse large B‐cell lymphoma, immune checkpoint, LAG3, LAG‐3, PD‐L1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Although some patients with diffuse large B‐cell lymphoma (DLBCL) show a response to immunotherapy, there are still many who do not respond. This suggests that various immune checkpoints are complicatedly intertwined in the composition of the tumor microenvironment of DLBCL. Patients and Methods To comprehensively understand the expression of various immune checkpoint genes in DLBCL, we performed NanoString assay in 98 patients to investigate 579 genes. In addition, we performed immunohistochemistry for LAG‐3 and PD‐L1 to compare the results with expression in NanoString assay. Results As a result of hierarchical clustering of NanoString assay, 98 DLBCLs were classified into three tumor immune microenvironment clusters. Most immune checkpoint genes showed the highest expression in cluster A and the lowest in cluster C. However, the expression of LAG3 was the highest in cluster C and the lowest in cluster A, showing an expression pattern opposite to that of other immune checkpoint genes. In Cluster A, the expression of genes related to T‐cell activity such as CD8A and GZMB was increased. In Cluster C, the expression of genes related to major histocompatibility complex molecules was the highest. Immunohistochemical stains showed modest agreement with the NanoString results but did not help clustering. Conclusion Our results show that the unique expression pattern of LAG3 in DLBCL contrasts with that of other immune checkpoints. We suggest that the combination of anti‐PD‐1/PD‐L1 and anti‐LAG‐3 blockades in the immunotherapy of DLBCL patients can have a synergistic effect, improving the immunotherapy efficacy and outcome in DLBCL patients.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-7634Test

الوصول الحر: https://doaj.org/article/4ce3c97660b24e068912b1aa4cba0da8Test

المؤلفون: Bediz Kurt İnci, Elif Acar, Fatih Gürler, Ayşegül İlhan, Fatih Yıldız, Fisun Ardıç, Berna Öksüzoğlu, Nuriye Özdemir, Ahmet Özet, Güldal Esendağlı, Ozan Yazıcı

المصدر: Journal of Clinical Medicine, Vol 13, Iss 12, p 3620 (2024)

مصطلحات موضوعية: sarcoma, OX40, TİM-3, LAG-3, PD-L1, Medicine

الوصف: Introduction: The current study aims to evaluate the OX40, TIM-3, LAG-3, and PD-L1 targeted pathways in the regulation of T-cell activity in sarcoma patients to determine their relationship with overall survival (OS). Method: This study included one hundred and eleven patients with bone and soft tissue sarcoma diagnosed in two centers between 2010 and 2020. OX40, LAG-3, TIM-3 and PD-L1 expression levels were evaluated immunohistochemically from pathology preparations. Results: PD-L1 staining was detected in tumor cells, OX40, LAG-3, TIM-3 staining was detected in inflammatory cells in tumor tissue. In univariate analysis, no significant relationship was found between OX40, TIM-3, LAG-3, and PD-L1 staining and overall survival (respectively: p = 0.12, p = 0.49, p = 0.31, p = 0.95). When grade and stage at diagnosis, which were found to be significant in univariate analysis, along with OX-40, TIM-3, LAG-3, and PD-L1, were evaluated in multivariate analysis, a positive effect of OX-40 staining on overall survival was determined (p = 0.009). Considering the correlation between PDL-1 and OX40, TIM-3, and LAG-3 staining, a significant positive correlation was found between PDL-1 and TIM-3 and LAG-3 staining (respectively; p = 0.002, p = 0.001). Conclusions: There was no significant relationship between the PDL-1 staining percentage of tumor cells and OX40, TIM-3, and LAG-3 staining in inflammatory cells with the OS of sarcoma patients. However, detecting a significant positive correlation between PDL-1 staining and TIM-3 and LAG-3 staining also holds promise for finding effective targetable combination therapies that can prolong survival in sarcoma patients in the future.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2077-0383/13/12/3620Test; https://doaj.org/toc/2077-0383Test

الوصول الحر: https://doaj.org/article/5e999b2478e1404e86faa7429e5db21bTest

المؤلفون: Jingjing Su, Yiting Fu, Zitong Cui, Zain Abidin, Jingsong Yuan, Xinmiao Zhang, Runmin Li, Chunzhen Zhao

المصدر: Frontiers in Pharmacology, Vol 14 (2024)

مصطلحات موضوعية: relatlimab, LAG-3 inhibitor, nivolumab, metastatic melanoma, immune checkpoint, Therapeutics. Pharmacology, RM1-950

الوصف: Relatlimab is a type of human immunoglobulin G4 monoclonal blocking antibody. It is the world’s first Lymphocyte-Activation Gene-3 (LAG-3) inhibitor and the third immune checkpoint inhibitor with clinical application, following PD-1 and CTLA-4. Relatlimab can bind to the LAG-3 receptor which blocks the interaction between LAG-3 and its ligand to reduce LAG-3 pathway-mediated immunosuppression and promote T-cell proliferation, inducing tumor cell death. On 18 March 2022, the U.S. FDA approved the fixed-dose combination of relatlimab developed by Bristol Myers Squibb with nivolumab, under the brand name Opdualag for the treatment of unresectable or metastatic melanoma in adult and pediatric patients aged 12 and older. This study comprehensively describes the mechanism of action and clinical trials of relatlimab and a brief overview of immune checkpoint drugs currently used for the treatment of melanoma.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fphar.2023.1349081/fullTest; https://doaj.org/toc/1663-9812Test

الوصول الحر: https://doaj.org/article/1d2b0ae21c3643408d076b9b33d7a148Test

المؤلفون: Rivoltini, Licia, Camisaschi, Chiara, Fucà, Giovanni, Paolini, Biagio, Vergani, Barbara, Beretta, Valeria, Damian, Silvia, Duca, Matteo, Cresta, Sara, Magni, Michele, Leone, Biagio Eugenio, Castelli, Chiara, de Braud, Filippo, De Santis, Francesca, Di Nicola, Massimo

المساهمون: Rivoltini, L, Camisaschi, C, Fucà, G, Paolini, B, Vergani, B, Beretta, V, Damian, S, Duca, M, Cresta, S, Magni, M, Leone, B, Castelli, C, de Braud, F, De Santis, F, Di Nicola, M

مصطلحات موضوعية: triple-negative breast cancer, PD-1, LAG-3

الوصف: In patients with advanced triple-negative breast cancer (TNBC), translational research efforts are needed to improve the clinical efficacy of immunotherapy with checkpoint inhibitors. Here, we report on the immunological characterization of an exceptional, long-lasting, tumor complete response in a patient with metastatic TNBC treated with dual PD-1 and LAG-3 blockade within the phase I/II study CLAG525X2101C (NCT02460224) The pre-treatment tumor biopsy revealed the presence of a CD3+ and CD8+ cell infiltrate, with few PD1+ cells, rare CD4+ cells, and an absence of both NK cells and LAG3 expression. Conversely, tumor cells exhibited positive staining for the three primary LAG-3 ligands (HLA-DR, FGL-1, and galectin-3), while being negative for PD-L1. In peripheral blood, baseline expression of LAG-3 and PD-1 was observed in circulating immune cells. Following treatment initiation, there was a rapid increase in proliferating granzyme-B+ NK and T cells, including CD4+ T cells, alongside a reduction in myeloid-derived suppressor cells. The role of LAG-3 expression on circulating NK cells, as well as the expression of LAG-3 ligands on tumor cells and the early modulation of circulating cytotoxic CD4+ T cells warrant further investigation as exploitable predictive biomarkers for dual PD-1 and LAG-3 blockade. Trial registration: NCT02460224. Registered 02/06/2015.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/38336861; info:eu-repo/semantics/altIdentifier/wos/WOS:001160750400058; volume:14; issue:1; journal:SCIENTIFIC REPORTS; https://hdl.handle.net/10281/460058Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85184786154

الإتاحة: https://doi.org/10.1038/s41598-024-54041-9Test
https://hdl.handle.net/10281/460058Test

المؤلفون: Mačak Šafranko, Željka, Jakopec, Lana, Svaguša, Karla, Cvetko Krajinović, Lidija, Tomasović, Domagoj, Lukić, Ljiljana, Markotić, Alemka

المصدر: https://www.mdpi.com/2075-1729/14/5/551Test ; Life ; Volume 14 ; Issue 5 ; ISSN 2075-1729 (Online.

مصطلحات موضوعية: orthohantavirus, HFRS, PUUV, inhibitory receptors, immune regulations, TIM-3, LAG-3, PD-1, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Infektologija, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Infectology

الوصف: Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease widespread in Europe and Asia. HFRS is caused by negative-sensed single-stranded RNA orthohantaviruses transmitted to humans through inhaling aerosolized excreta of infected rodents. Symptoms of HFRS include acute kidney injury, thrombocytopenia, hemorrhages, and hypotension. The immune response raised against viral antigens plays an important role in the pathogenesis of HFRS. Inhibitory co-receptors are essential in regulating immune responses, mitigating immunopathogenesis, and reducing tissue damage. Our research showed an increased soluble form of inhibitory co-receptors TIM-3, LAG-3, and PD-1 in HFRS patients associated with disease severity. Our study aimed to investigate the impact of HFRS on the concentrations of soluble forms of inhibitory receptors TIM-3, LAG-3, and PD-1 in the patient’s serum and the potential correlation with key clinical parameters. Our study aimed to investigate the impact of HFRS on the concentrations of soluble forms of inhibitory receptors TIM-3, LAG-3, and PD-1 in the patient’s serum and their possible association with relevant clinical parameters. Using multiplex immunoassay, we found elevated levels of TIM-3, LAG-3, and PD-1 proteins in the serum of HFRS patients. Furthermore, increased levels were associated with creatinine, urea, lactate dehydrogenase concentrations, and platelet count. These findings suggest that these proteins play a role in regulating the immune response and disease progression.

وصف الملف: application/pdf

العلاقة: Sveučilište u Rijeci. Medicinski fakultet. Katedra za zarazne bolesti.; University of Rijeka. Faculty of Medicine. Department of Infectious Diseases.; https://www.unirepository.svkri.uniri.hr/islandora/object/medri:8567Test; https://urn.nsk.hr/urn:nbn:hr:184:230383Test; https://www.unirepository.svkri.uniri.hr/islandora/object/medri:8567/datastream/FILE0Test

الإتاحة: https://doi.org/10.3390/life14050551Test
https://www.unirepository.svkri.uniri.hr/islandora/object/medri:8567Test
https://urn.nsk.hr/urn:nbn:hr:184:230383Test
https://www.unirepository.svkri.uniri.hr/islandora/object/medri:8567/datastream/FILE0Test

المؤلفون: Rodriguez Guilarte, Linmar Eri Jose, Ramirez Pozo, Mario Andres, Andrade Parra, Catalina Andrea, Kalergis Parra Alexis Mikes

مصطلحات موضوعية: LAG-3, Ligand, T cell dysfunction, Viral infections, Medicina y salud, 03 Good Health and Well-being, 03 Salud y bienestar

الوقت: 610

الوصف: LAG-3 is a type I transmembrane protein expressed on immune cells, such as activated T cells, and binds to MHC class II with high affinity. LAG-3 is an inhibitory receptor, and its multiple biological activities on T cell activation and effector functions play a regulatory role in the immune response. Immunotherapies directed at immune checkpoints, including LAG-3, have become a promising strategy for controlling malignant tumors and chronic viral diseases. Several studies have suggested an association between the expression of LAG-3 with an inadequate immune response during respiratory viral infections and the susceptibility to reinfections, which might be a consequence of the inhibition of T cell effector functions. However, important information relative to therapeutic potential during acute viral lower respiratory tract infections and the mechanism of action of the LAG-3 checkpoint remains to be characterized. In this article, we discuss the contribution of LAG-3 to the impairment of T cells during viral respiratory infections. Understanding the host immune response to respiratory infections is crucial for developing effective vaccines and therapies.

وصف الملف: 15 páginas; application/pdf

العلاقة: https://doi.org/10.3390/v15010147Test; https://repositorio.uc.cl/handle/11534/80992Test; WOS:000926169300001

الإتاحة: https://doi.org/10.3390/v15010147Test
https://repositorio.uc.cl/handle/11534/80992Test

المؤلفون: Anastasia Sergeevna Belevich, M. I. Yarmolinskaya, Sergey Alekseevich Selkov, Dmitriy Igorevich Sokolov, Анастасия Сергеевна Белевич, М. И. Ярмолинская, Сергей Алексеевич Сельков, Дмитрий Игоревич Соколов

المساهمون: Работы выполнена в рамках ФНИ № 122041500063-2

المصدر: Medical Immunology (Russia); Online First ; Медицинская иммунология; Online First ; 2313-741X ; 1563-0625 ; 10.15789/1563-0625-0-0

مصطلحات موضوعية: контрольные точки, эндометриоз, CTLA-4, PD-1, LAG-3, Tim-3, TIGIT, 4-1BB, GITR

الوصف: Наружный генитальный эндометриоз – хроническое рецидивирующее заболевание, патогенез которого остается до конца не изученным. Эндометриоз делит общие черты с опухолевым процессом. Так, для данного заболевания характерно распространение ткани, подобной эндометрию, вне полости матки. Пролиферация и инвазия клеток в эктопических очагах возможна только при нарушении местных процессов иммунной защиты. Одним из механизмов избегания иммунологического надзора, доказанным для опухолевого процесса, является использование контрольных точек. Контрольные точки представляют собой белки, расположенные на поверхности клеток иммунной системы (преимущественно Т-лимфоцитов). Связывание контрольных точек с их лигандами на поверхности опухолевой клетки приводит к ингибированию клеток иммунитета и помогает таким образом опухоли «выжить». В данном обзоре собраны данные литературы об известных на сегодняшний день контрольных точках: CTLA-4, PD-1, LAG-3, Tim-3, TIGIT, 4-1BB, GITR. Рассмотрены наиболее изученные их лиганды такие как (CD80/CD86, PD-1L, Gal-3, Gal-9). В обзоре систематизированы данные о клетках, на которых экспрессируются контрольные точки и их белки с ними связывающиеся, приведены примеры опухолей, которые используют данное взаимодействие для защиты от распознавания. Помимо этого, в обзоре описаны препараты – ингибиторы контрольных точек, успешно используемые в терапии определенных опухолей. Наряду с отсутствием полноты знаний о патогенезе эндометриоза, на сегодняшний день единственным достоверным методом его диагностики является проведение лапароскопии с визуализацией очагов и последующим их гистологическим исследованием. В обзоре собраны результаты исследований, посвященных изучению некоторых биомаркеров для неинвазивной диагностики эндометриоза: CA-125, MCP-1, IL-6, BDNF и других. Авторами рассмотрены результаты нескольких работ, в которых иммунные контрольные точки изучались в аспекте наружного генитального эндометриоза. Следует подчеркнуть, что по результатам этих исследований экспрессия контрольных точек ...

وصف الملف: application/pdf

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الإتاحة: https://doi.org/10.15789/1563-0625-CIT-2923Test
https://doi.org/10.15789/1563-0625-0-0Test
https://www.mimmun.ru/mimmun/article/view/2923Test

المؤلفون: Li, Yu-Quan, Chen, Xue-Mei, Si, Gui-Fei, Yuan, Xue-Min

المصدر: Biomolecules and Biomedicine; Advanced online ; 2831-090X ; 2831-0896

مصطلحات موضوعية: Immunotherapy, programmed cell death protein 1 (PD-1), programmed cell death protein 1 ligand 1 (PD-L1), lymphocyte activation gene-3 (LAG-3), combination therapy

الوصف: The application of immune checkpoint inhibitors has proven to be an effective treatment for cancer. Immune checkpoints such as programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T-cell immunoglobulin-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene-3 (LAG-3) have received extensive attention, and the efficacy of antibodies or inhibitors against these checkpoints (either alone or in combination) has been evaluated in many tumors. This paper provides a brief overview of the PD-1 and LAG-3 checkpoints, and then shifts focus to the combined use of PD-1 and LAG-3 antibodies in both in vivo and in vitro experiments. In the in vitro experiments, we examined the correlation between the expression and activation of these inhibitors on T cells, and also assessed toxicity in animals in preparation for in vivo experiments. The effects of the combined use of PD-1 and LAG-3 antibodies were then summarized in animal models of melanoma, MC38 carcinoma, and other tumors. In clinical studies, the combined application of these antibodies was assessed in patients with melanoma, colorectal, breast, and renal cell cancers, as well as other solid tumors. In general, the combination of PD-1 and LAG-3 antibodies has shown promising results in both in vivo and in vitro studies.

وصف الملف: application/pdf

العلاقة: https://www.bjbms.org/ojs/index.php/bjbms/article/view/10339/3222Test; https://www.bjbms.org/ojs/index.php/bjbms/article/view/10339Test

الإتاحة: https://doi.org/10.17305/bb.2024.10339Test
https://www.bjbms.org/ojs/index.php/bjbms/article/view/10339Test

المؤلفون: Fumio Takizawa, Keiichiro Hashimoto, Ryuichiro Miyazawa, Yuko Ohta, Ana Veríssimo, Martin F. Flajnik, David Parra, Kotaro Tokunaga, Hiroaki Suetake, J. Oriol Sunyer, Johannes M. Dijkstra

المصدر: Frontiers in Immunology, Vol 14 (2023)

مصطلحات موضوعية: CD4, LAG-3, evolution, shark, cytoplasmic tail, activation motif, Immunologic diseases. Allergy, RC581-607

الوصف: CD4 and LAG-3 are related molecules that are receptors for MHC class II molecules. Their major functional differences are situated in their cytoplasmic tails, in which CD4 has an activation motif and LAG-3 an inhibitory motif. Here, we identify shark LAG-3 and show that a previously identified shark CD4-like gene has a genomic location, expression pattern, and motifs similar to CD4 in other vertebrates. In nurse shark (Ginglymostoma cirratum) and cloudy catshark (Scyliorhinus torazame), the highest CD4 expression was consistently found in the thymus whereas such was not the case for LAG-3. Throughout jawed vertebrates, the CD4 cytoplasmic tail possesses a Cx(C/H) motif for binding kinase LCK, and the LAG-3 cytoplasmic tail possesses (F/Y)xxL(D/E) including the previously determined FxxL inhibitory motif resembling an immunoreceptor tyrosine-based inhibition motif (ITIM). On the other hand, the acidic end of the mammalian LAG-3 cytoplasmic tail, which is believed to have an inhibitory function as well, was acquired later in evolution. The present study also identified CD4-1, CD4-2, and LAG-3 in the primitive ray-finned fishes bichirs, sturgeons, and gars, and experimentally determined these sequences for sterlet sturgeon (Acipenser ruthenus). Therefore, with CD4-1 and CD4-2 already known in teleosts (modern ray-finned fish), these two CD4 lineages have now been found within all major clades of ray-finned fish. Although different from each other, the cytoplasmic tails of ray-finned fish CD4-1 and chondrichthyan CD4 not only contain the Cx(C/H) motif but also an additional highly conserved motif which we expect to confer a function. Thus, although restricted to some species and gene copies, in evolution both CD4 and LAG-3 molecules appear to have acquired functional motifs besides their canonical Cx(C/H) and ITIM-like motifs, respectively. The presence of CD4 and LAG-3 molecules with seemingly opposing functions from the level of sharks, the oldest living vertebrates with a human-like adaptive immune system, underlines their importance for the jawed vertebrate immune system. It also emphasizes the general need of the immune system to always find a balance, leading to trade-offs, between activating and inhibiting processes.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1267743/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/de4d4f3355de47cb9c19eab95512dd69Test

المؤلفون: Tuba N. Gide, Elizabeth C. Paver, Zarwa Yaseen, Nigel Maher, Nurudeen Adegoke, Alexander M. Menzies, Ines Pires da Silva, James S. Wilmott, Georgina V. Long, Richard A. Scolyer

المصدر: OncoImmunology, Vol 12, Iss 1 (2023)

مصطلحات موضوعية: LAG-3, biomarker, immune checkpoint inhibitors, immunotherapy, melanoma, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: ABSTRACTLymphocyte-activation gene-3 (LAG-3), an immune checkpoint receptor, negatively regulates T-cell function and facilitates immune escape of tumors. Dual inhibition of LAG-3 and programmed cell death receptor-1 (PD-1) significantly improved progression-free survival (PFS) in metastatic melanoma patients compared to anti-PD-1 therapy alone. Investigating the utility of LAG-3 expression as a biomarker of response to anti-LAG-3 + anti-PD-1 immunotherapy is of great clinical relevance. This study sought to evaluate the association between baseline LAG-3 expression and clinical outcomes following anti-LAG-3 and anti-PD-1-based immunotherapy in metastatic melanoma. LAG-3 immunohistochemistry (clone D2G4O) was performed on pre-treatment formalin-fixed, paraffin-embedded metastatic melanoma specimens from 53 patients treated with combination anti-LAG-3 + anti-PD-1-based therapies. Eleven patients had received prior anti-PD-1-based treatment. Patients were categorized as responders (complete/partial response; n = 36) or non-responders (stable/progressive disease; n = 17) based on the Response Evaluation Criteria in Solid Tumours (RECIST). Tumor-infiltrating lymphocytes (TILs) were scored on hematoxylin and eosin-stained sections. LAG-3 expression was observed in 81% of patients, with staining in TILs and dendritic cells. Responders displayed significantly higher proportions of LAG-3+ cells compared to non-responders (P = .0210). LAG-3 expression positively correlated with TIL score (P .05). Patients with ≥ 1% LAG-3+ cells in their tumors had significantly longer PFS compared to patients with

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2162-402XTest

الوصول الحر: https://doaj.org/article/de51474a80d24f65bee9d63be6c7447fTest