المؤلفون: Fei Chu, Nicholas J. Skertich, Jeffrey A. Borgia, Imad Tarhoni, Stephen Szajek, Mary Beth Madonna

المصدر: Surgery Open Science, Vol 6, Iss, Pp 10-14 (2021)
Surgery Open Science

مصطلحات موضوعية: WT, wild type, Herpesvirus entry mediator, CD80, cluster of differentiation 80, TLR-2, Toll like receptor 2, RD1-811, PD-L1, programmed death ligand 1, GITRL, ligand for receptor TNFRSF18/AITR/GITR, CTLA-4, cytotoxic T-lymphocyte-associated protein 4, ICOS, inducible T-cell costimulatory (ICOS), BTLA, B- and T-lymphocyte attenuator, Biology, Article, DoxR, doxorubicin resistant, Western blot, medicine, PD-L2, programmed death ligand 2, HVEM, herpesvirus entry mediator, TIM-3, T-cell immunoglobulin-3, Matrigel, LAG-3, lymphocyte-activation gene-3, CD40, cluster of differentiation 40, Cluster of differentiation, medicine.diagnostic_test, CD86, cluster of differentiation 86, CD27, cluster of differentiation 27, GITR, glucocorticoid-induced TNFR-related protein, Ligand (biochemistry), medicine.disease, PD-1, programmed death 1, FDA, Food and Drug Administration, In vitro, Cell culture, CD28, cluster of differentiation 28, Cancer research, Osteosarcoma, Surgery

الوصف: Background: Inhibition of the programmed death ligand 1, programmed death 1 pathway has been successfully used for treatment of multiple advanced adult cancers. However, its use in pediatric osteosarcoma is still in its infancy. In this study, we investigated programmed death ligand 1 and other checkpoint molecules' expression to determine the potential usefulness as targets for drug therapy. Methods: We incubated human wild-type osteosarcoma cells with incremental concentrations of doxorubicin to create a doxorubicin-resistant cell line. Matrigel in vitro invasion assays were used to compare invasiveness. Comparative programmed death ligand 1 expression was evaluated by Western blot assays. An immuno-oncology checkpoint protein panel was used to compare concentrations of 16 other checkpoint molecules. Chi-square tests and Wilcoxon rank-sum tests were used to determine significant differences. Results: A doxorubicin-resistant cell line was successfully created and was significantly more invasive than wild-type cells (0.47 vs 0.07, P < .001). On Western blot assay, doxorubicin-resistant but not wild-type cells expressed programmed death ligand 1. Doxorubicin-resistant cells had significantly higher levels of T-cell immunoglobulin-3 and cluster of differentiation 86 and higher cluster of differentiation 27, cluster of differentiation 40, lymphocyte-activation gene-3, cluster of differentiation 80, programmed death ligand 1, programmed death ligand 2, and inducible T-cell costimulatory expression than wild-type cells. Both lines expressed B- and T-lymphocyte attenuator, cluster of differentiation 28, herpesvirus entry mediator, and programmed death 1. Herpesvirus entry mediator, cluster of differentiation 40, and programmed death ligand 2 were also present in the culture media of both cell lines. Conclusion: Doxorubicin-resistant osteosarcoma seems to express higher programmed death ligand 1 than nonresistant wild-type cells. Benchmarking checkpoint molecules may provide the basis for future studies that elucidate pathways of drug resistance and tumor metastasis, biomarkers for cancer prognosis or recurrence, and future targets for directed drug therapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6f4b311880ebd1fc0b8ba946d799acefTest
http://www.sciencedirect.com/science/article/pii/S2589845021000129Test

المؤلفون: Mingfang Zhao, Ruoyu Wang, Heming Li, Wenjing Qian

المصدر: Journal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-17 (2021)
Journal of Hematology & Oncology

مصطلحات موضوعية: Cancer Research, medicine.medical_specialty, Programmed cell death, LAG3, Epithelial-Mesenchymal Transition, medicine.drug_class, Review, Biology, Monoclonal antibody, Antigens, CD, LAG-3, Internal medicine, Neoplasms, medicine, Animals, Humans, Diseases of the blood and blood-forming organs, Epithelial–mesenchymal transition, Molecular Targeted Therapy, Molecular Biology, Immune Checkpoint Inhibitors, FGL1, RC254-282, Hematology, Fibrinogen, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Biomarker, Ligand (biochemistry), Lymphocyte Activation Gene 3 Protein, Immune checkpoint, Oncology, Cancer research, Biomarker (medicine), Immune resistance, Tumor Escape, Immunotherapy, RC633-647.5, Immune checkpoint blockade

الوصف: Immune checkpoint therapy has achieved significant efficacy by blocking inhibitory pathways to release the function of T lymphocytes. In the clinic, anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs) have progressed to first-line monotherapies in certain tumor types. However, the efficacy of anti-PD-1/PD-L1 mAbs is still limited due to toxic side effects and de novo or adaptive resistance. Moreover, other immune checkpoint target and biomarkers for therapeutic response prediction are still lacking; as a biomarker, the PD-L1 (CD274, B7-H1) expression level is not as accurate as required. Hence, it is necessary to seek more representative predictive molecules and potential target molecules for immune checkpoint therapy. Fibrinogen-like protein 1 (FGL1) is a proliferation- and metabolism-related protein secreted by the liver. Multiple studies have confirmed that FGL1 is a newly emerging checkpoint ligand of lymphocyte activation gene 3 (LAG3), emphasizing the potential of targeting FGL1/LAG3 as the next generation of immune checkpoint therapy. In this review, we summarize the substantial regulation mechanisms of FGL1 in physiological and pathological conditions, especially tumor epithelial to mesenchymal transition, immune escape and immune checkpoint blockade resistance, to provide insights for targeting FGL1 in cancer treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c863141164b6748972c800d80e9c95f0Test
https://doaj.org/article/bde087ed0c634ef7af10c3e368eb935bTest

المؤلفون: Littringer, Katharina, Moresi, Claudia, Rakebrandt, Nikolas, Zhou, Xiaobei, Schorer, Michelle, Dolowschiak, Tamas, Kirchner, Florian, Rost, Felix, Keller, Christian W, McHugh, Donal, LeibundGut-Landmann, Salomé, Robinson, Mark D, Joller, Nicole

المصدر: Littringer, Katharina; Moresi, Claudia; Rakebrandt, Nikolas; Zhou, Xiaobei; Schorer, Michelle; Dolowschiak, Tamas; Kirchner, Florian; Rost, Felix; Keller, Christian W; McHugh, Donal; LeibundGut-Landmann, Salomé; Robinson, Mark D; Joller, Nicole (2018). Common features of regulatory T cell specialization during Th1 responses. Frontiers in Immunology, 9:1344.

مصطلحات موضوعية: Institute of Molecular Life Sciences, Institute of Virology, Institute of Experimental Immunology, 570 Life sciences, biology, CD85k, CXCR3, Lag-3, T-bet, Th1, Treg cells, co-inhibitory receptors

الوصف: CD4+Foxp3+ Treg cells are essential for maintaining self-tolerance and preventing excessive immune responses. In the context of Th1 immune responses, co-expression of the Th1 transcription factor T-bet with Foxp3 is essential for Treg cells to control Th1 responses. T-bet-dependent expression of CXCR3 directs Treg cells to the site of inflammation. However, the suppressive mediators enabling effective control of Th1 responses at this site are unknown. In this study, we determined the signature of CXCR3+ Treg cells arising in Th1 settings and defined universal features of Treg cells in this context using multiple Th1-dominated infection models. Our analysis defined a set of Th1-specific co-inhibitory receptors and cytotoxic molecules that are specifically expressed in Treg cells during Th1 immune responses in mice and humans. Among these, we identified the novel co-inhibitory receptor CD85k as a functional predictor for Treg-mediated suppression specifically of Th1 responses, which could be explored therapeutically for selective immune suppression in autoimmunity.

وصف الملف: application/pdf

العلاقة: https://www.zora.uzh.ch/id/eprint/152029/1/PU584.pdfTest; info:pmid/29951069; urn:issn:1664-3224

الإتاحة: https://doi.org/10.5167/uzh-15202910.3389/fimmu.2018.01344Test
https://www.zora.uzh.ch/id/eprint/152029Test/
https://www.zora.uzh.ch/id/eprint/152029/1/PU584.pdfTest

المؤلفون: Katharina Feldmann, Adelheid Wöhrer, Maximilian J. Mair, Barbara Kiesel, Matthias Preusser, Anna S. Berghoff, Leonhard Müllauer, Karin Dieckmann, Georg Widhalm

المصدر: Journal of Neuro-Oncology

مصطلحات موضوعية: Cancer Research, medicine.medical_treatment, Programmed Cell Death 1 Receptor, chemical and pharmacologic phenomena, B7-H1 Antigen, Diffuse Glioma, Lymphocytes, Tumor-Infiltrating, Immune system, Antigens, CD, LAG-3, Glioma, medicine, Humans, Immune Checkpoint Inhibitors, CD20, Tumor microenvironment, biology, business.industry, Immunotherapy, Prognosis, medicine.disease, Lymphocyte Activation Gene 3 Protein, Immune checkpoint, Neurology, Oncology, Monoclonal, Clinical Study, Cancer research, biology.protein, Neurology (clinical), Glioblastoma, business

الوصف: Purpose Immune modulatory therapies including immune checkpoint inhibitors have so far failed to result in clinically meaningful efficacy in glioma. We aimed to investigate lymphocyte activation gene 3 (LAG-3), an inhibitory receptor on immune cells and target of second-generation immune checkpoint inhibitors, in glioma. Methods 97 patients with diffuse glioma (68 with glioblastoma, 29 with WHO grade II-III glioma) were identified from the Neuro-Biobank of the Medical University of Vienna. LAG-3 expression in the inflammatory microenvironment was assessed by immunohistochemistry (monoclonal anti-LAG-3 antibody, clone 17B4) and correlated to CD3+ , CD8+ , CD20+ and PD-1+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression on tumor cells. Results LAG-3+ TILs could be observed in 10/97 (10.3%) IDH-wildtype samples and in none of the included IDH-mutant glioma samples (p = 0.057). Further, LAG-3+ TILs were only observed in WHO grade IV glioblastoma, while none of the investigated WHO grade II–III glioma presented with LAG-3+ TILs (p = 0.03). No association of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and presence of LAG-3+ TILs was observed (p = 0.726). LAG-3 expression was associated with the presence of CD3+ (p = 0.029), CD8+ (p = 0.001), PD-1+ (p Conclusions LAG-3 is only rarely expressed on TILs in IDH-wildtype glioma and associated with active inflammatory milieu as defined by higher TIL density. Immune microenvironment diversity should be considered in the design of future immunotherapy trials in glioma.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::db6d8bf816fa704128a06a915cfa36c1Test
https://doi.org/10.1007/s11060-021-03721-xTest

المؤلفون: Zul Fazreen, Kosaku Mimura, Nicholas Syn, Yuko Nakayama, Jin-Fen Xiao, Wei Peng Yong, Richie Soong, Koji Kono, Bernadette Reyna Asuncion, Ley-Fang Kua

المصدر: Gastric Cancer

مصطلحات موضوعية: Male, 0301 basic medicine, Cancer Research, medicine.medical_treatment, T cell, Programmed Cell Death 1 Receptor, Tim-3, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigens, CD, Stomach Neoplasms, Cell Line, Tumor, PD-L1, PD-1, Humans, Medicine, Cytotoxic T cell, Lectins, C-Type, Cytotoxicity, Aged, Singapore, MHC class II, biology, business.industry, Lag-3, Gastroenterology, General Medicine, Immunotherapy, Survival Analysis, Gene Expression Regulation, Neoplastic, CTL, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Original Article, Combinatorial immunotherapy, Female, Gastric cancer, business, Cell Adhesion Molecules

الوصف: Background Immunotherapy targeting PD-1 provides a limited survival benefit in patients with unresectable advanced or recurrent gastric cancer (GC). Beside PD-L1, the expression of inhibitory ligands such as CEACAM-1 and LSECtin on GC cells account for this limitation. Here we assessed their expression and immune suppressive effect in GC patients. Methods Using multiplexed immunohistochemistry staining, we evaluated the distribution of different inhibitory ligands, including PD-L1, CEACAM-1, LSECtin, and MHC class II, in 365 GC patients. We analyzed their correlations and overall survival (OS) based on the expression of each inhibitory ligand and the independent prognostic factors that affect OS. Subsequently, we evaluated the additive effect of anti-PD-1 mAb or anti-PD-L1 mAb with/without anti-Lag-3 mAb with/without anti-Tim-3 mAb in cytotoxic assay using tumor-antigen specific CTL clones against GC cell lines. Results Co-expression of the inhibitory ligands for PD-1, Tim-3, and Lag-3 was observed in the largest proportion (34.7%). CEACAM-1, LSECtin, and MHC class II expression showed significant correlation with PD-L1 expression and OS. Multivariable analysis demonstrated that CEACAM-1 low is an independent prognostic factor. Furthermore, combining dual and triple ICIs yielded additive effect on cytotoxicity of CTL clones against each immune inhibitory ligand positive GC cell lines. Conclusions Our findings suggested that the expression of inhibitory ligands for Tim-3 and Lag-3 on GC cells serve as potential biomarkers to predict the response to anti-PD-1 therapy and the combinatorial immunotherapy with ICIs targeting for PD-1, Tim-3, and Lag-3 has a therapeutic potential for GC patients.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7b04fb8da0f849665868f13e779a7156Test
https://doi.org/10.1007/s10120-020-01151-8Test

المؤلفون: Georgina H. Mason, David K. Cole, Frédéric Triebel, Awen Gallimore, Andrew James Godkin, Bruce J. MacLachlan, Alexander Greenshields-Watson

المصدر: European Journal of Immunology

مصطلحات موضوعية: 0301 basic medicine, Molecular immunology and signaling, LAG3, T-Lymphocytes, medicine.medical_treatment, T cell, Immunology, Cell, T cells, Receptors, Antigen, T-Cell, Biology, immune checkpoint inhibitors, Jurkat Cells, 03 medical and health sciences, 0302 clinical medicine, LAG‐3, Costimulatory and Inhibitory T-Cell Receptors, Downregulation and upregulation, Cancer immunotherapy, Antigens, CD, HLA Antigens, Cell Line, Tumor, Neoplasms, medicine, Humans, Immunology and Allergy, Basic, Receptor, Research Articles, cancer immunotherapy, Lymphocyte Activation Gene 3 Protein, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, CD4 Antigens, pHLA‐II, biology.protein, Research Article|Basic, Antibody, Function (biology), 030215 immunology

الوصف: Immune checkpoint inhibitors (antibodies that block the T cell co‐inhibitory receptors PD‐1/PD‐L1 or CTLA‐4) have revolutionized the treatment of some forms of cancer. Importantly, combination approaches using drugs that target both pathways have been shown to boost the efficacy of such treatments. Subsequently, several other T cell inhibitory receptors have been identified for the development of novel immune checkpoint inhibitors. Included in this list is the co‐inhibitory receptor lymphocyte activation gene‐3 (LAG‐3), which is upregulated on T cells extracted from tumor sites that have suppressive or exhausted phenotypes. However, the molecular rules that govern the function of LAG‐3 are still not understood. Using surface plasmon resonance combined with a novel bead‐based assay (AlphaScreenTM), we demonstrate that LAG‐3 can directly and specifically interact with intact human leukocyte antigen class II (HLA‐II) heterodimers. Unlike the homologue CD4, which has an immeasurably weak affinity using these biophysical approaches, LAG‐3 binds with low micromolar affinity. We further validated the interaction at the cell surface by staining LAG‐3+ cells with pHLA‐II‐multimers. These data provide new insights into the mechanism by which LAG‐3 initiates T cell inhibition.
We demonstrate that human LAG‐3 binds directly to peptide‐human leukocyte antigen class II complex (pHLA‐II) with low micromolar affinity. These findings provide new insights into the mechanism by which LAG‐3 initiates T cell inhibition and has implication for the development of novel immune checkpoint inhibitors for cancer immunotherapy.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::295dfce87346771adca4707fe21a976bTest
https://doi.org/10.1002/eji.202048753Test

المؤلفون: Janik Puttemans, Marleen Keyaerts, Pieterjan Debie, Nick Devoogdt, L. De Beck, Thomas Ertveldt, Cleo Goyvaerts, Geert Raes, Quentin Lecocq, Karine Breckpot, Robin Maximilian Awad, Y. De Vlaeminck

المساهمون: Laboratory of Molecullar and Cellular Therapy, Faculty of Medicine and Pharmacy, Medical Imaging, Clinical sciences, Supporting clinical sciences, Basic (bio-) Medical Sciences, Department of Bio-engineering Sciences, Cellular and Molecular Immunology, Nuclear Medicine

المصدر: EJNMMI Research, Vol 11, Iss 1, Pp 1-13 (2021)
EJNMMI Research

مصطلحات موضوعية: Single-domain antibody, medicine.medical_treatment, R895-920, Molecular imaging, Medical physics. Medical radiology. Nuclear medicine, LAG-3, Medicine, Radiology, Nuclear Medicine and imaging, Receptor, Lung cancer, immune checkpoint, Original Research, Cancer, biology, business.industry, Melanoma, Immunotherapy, medicine.disease, Immune checkpoint, Lymphocyte activation gene-3, Cancer research, biology.protein, Nanobody, immunotherapy, Antibody, business

الوصف: Recent advancements in the field of immune-oncology have led to a significant increase in life expectancy of patients with diverse forms of cancer, such as hematologic malignancies, melanoma and lung cancer. Unfortunately, these encouraging results are not observed in the majority of patients, who remain unresponsive and/or encounter adverse events. Currently, researchers are collecting more insight into the cellular and molecular mechanisms that underlie these variable responses. As an example, the human lymphocyte activation gene-3 (huLAG-3), an inhibitory immune checkpoint receptor, is increasingly studied as a therapeutic target in immune-oncology. Noninvasive molecular imaging of the immune checkpoint programmed death protein-1 (PD-1) or its ligand PD-L1 has shown its value as a strategy to guide and monitor PD-1/PD-L1-targeted immune checkpoint therapy. Yet, radiotracers that allow dynamic, whole body imaging of huLAG-3 expression are not yet described. We here developed single-domain antibodies (sdAbs) that bind huLAG-3 and showed that these sdAbs can image huLAG-3 in tumors, therefore representing promising tools for further development into clinically applicable radiotracers. Supplementary Information The online version contains supplementary material available at 10.1186/s13550-021-00857-9.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::867ec67d785e9c2e394420ce275bd7d7Test
https://doi.org/10.1186/s13550-021-00857-9Test

المؤلفون: Quentin Lecocq, Karine Breckpot, Geert Raes, Marleen Keyaerts, Cleo Goyvaerts, Kris Thielemans, Yannick De Vlaeminck, Robin Maximilian Awad, Thomas Ertveldt, Wout De Mey, Nick Devoogdt

المساهمون: Laboratory of Molecullar and Cellular Therapy, Faculty of Medicine and Pharmacy, Basic (bio-) Medical Sciences, Department of Bio-engineering Sciences, Cellular and Molecular Immunology, Vriendenkring VUB, Supporting clinical sciences, Medical Imaging, Nuclear Medicine

مصطلحات موضوعية: single domain antibody, Programmed Cell Death 1 Receptor, Immunology, Immune system, Lymphocytes, Tumor-Infiltrating, Downregulation and upregulation, LAG-3, Blocking antibody, Medicine, Humans, Radiology, Nuclear Medicine and imaging, immune checkpoint, Cancer, nuclear imaging, biology, business.industry, Single-Domain Antibodies, medicine.disease, Immune checkpoint, Blockade, Radiology Nuclear Medicine and imaging, biology.protein, Cancer research, Nanobody, Antibody, Molecular imaging, business

الوصف: Recent advances in the field of immune-oncology led to the discovery of next-generation immune checkpoints (ICPs). Lymphocyte activation gene-3 (LAG-3), being the most widely studied among them, is being explored as a target for the treatment of cancer patients. Several antagonistic anti-LAG-3 antibodies are being developed and are prime candidates for clinical application. Furthermore, validated therapies targeting cytotoxic T-lymphocyte-associated protein-4, programmed cell-death protein-1, or programmed cell-death ligand-1 showed that only subsets of patients respond. This finding highlights the need for better tools for patient selection and monitoring. The potential of molecular imaging to detect ICPs noninvasively in cancer is supported by several preclinical and clinical studies. Here, we report on a single-domain antibody to evaluate whole-body LAG-3 expression in various syngeneic mouse cancer models using nuclear imaging. Methods: SPECT/CT scans of tumor-bearing mice were performed 1 h after injection with radiolabeled single-domain antibody. Organs and tumors of mice were isolated and evaluated for the presence of the radiolabeled tracer and LAG-3-expressing immune cells using a γ-counter and flow cytometry respectively. PD-1/LAG-3-blocking antibodies were injected in MC38-bearing mice. Results: The radiolabeled single-domain antibody detected LAG-3 expression on tumor-infiltrating lymphocytes (TILs) as soon as 1 h after injection in MC38, MO4, and TC-1 cancer models. The single-domain antibody tracer visualized a compensatory upregulation of LAG-3 on TILs in MC38 tumors of mice treated with PD-1-blocking antibodies. When PD-1 blockade was combined with LAG-3 blockade, a synergistic effect on tumor growth delay was observed. Conclusion: These findings consolidate LAG-3 as a next-generation ICP and support the use of single-domain antibodies as tools to noninvasively monitor the dynamic evolution of LAG-3 expression by TILs, which could be exploited to predict therapy outcome.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::54e4f60f96e8137e7509229a2545348aTest
https://hdl.handle.net/20.500.14017/949d9ece-83fb-4432-a911-77eb0678aa27Test

المؤلفون: Xiaohui Pan, Bo Yang, Hongjie Guo, Shuyuan Cheng, Xi Chen, Ling Ding, Qiaojun He, Wenxin Zhang

المصدر: Acta Pharmaceutica Sinica B, Vol 10, Iss 5, Pp 723-733 (2020)
Acta Pharmaceutica Sinica. B

مصطلحات موضوعية: TIM-3, T cell immunoglobulin and mucin domain 3, H3K27me3, tri-methylation of lysine 27 on histone H3, MDSCs, myeloid-derived suppressor cells, medicine.medical_treatment, Review, TAA, tumor-associated antigen, DC, dendritic cell, 0302 clinical medicine, EZH2, enhancer of zeste homolog 2, LAG-3, lymphocyte activation gene-3, CTLA-4, cytotoxic T lymphocyte antigen 4, Medicine, BETi, bromodomain and extra-terminal motif inhibitors, General Pharmacology, Toxicology and Pharmaceutics, FOXP3, forkhead box P3, HDACi, histone deacetylase inhibitor, Cancer, 0303 health sciences, ACE1, angiotensin converting enzyme, CLL, chronic lymphocytic leukemia, biology, IDO, indoleamine 2,3-dioxygenase, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Tregs, regulatory T cells, PD-L1/PD-1 blockade, CCL22 (MDC), macrophage-derived chemokine, Immunotherapy, TET2, ten-eleven translocation 2, CTLs, cytotoxic T lymphocytes, FDA, U. S. Food and Drug Administration, PD-L1, programmed cell death ligand 1, T cell, CTA, cancer testis antigen, Immune cycle, TIL, tumor infiltrating lymphocytes, Epigenetic regulation, OS, overall survival, 03 medical and health sciences, Immune system, Antigen, PD-L1, TH-1, T helper type 1, DNMT1, DNA methyltransferase 1, MHC, major histocompatibility complex, CX3CL1, C-X3-C motif chemokine ligand 1, IFN-γ, interferon-gamma, 030304 developmental biology, business.industry, lcsh:RM1-950, biochemical phenomena, metabolism, and nutrition, medicine.disease, CXCL, CXC chemokine ligand, Blockade, lcsh:Therapeutics. Pharmacology, APC, antigen-presenting cell, UHRF1, ubiquitin-like PHD and RING finger domain-containing 1, 5-AzaC, 5-azacitidine, ACP1, human red cell acid phosphatase, biology.protein, Cancer research, bacteria, DNMTi, DNA methyltransferase inhibitors, PD-1, programmed cell death 1, business, PRC2, polycomb repressive complex 2

الوصف: Immunotherapy strategies targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. However, owing to the heterogeneity of tumors and individual immune systems, PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients. Accumulating evidence has shown that an effective response to anti-PD-L1/anti-PD-1 therapy requires establishing an integrated immune cycle. Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. Impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating T cell trafficking and reactivation. Thus, a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.
Graphical abstract An effective response to anti-PD-L1/anti-PD-1 therapy requires the establishment of an integrated immune cycle. Impaired immune cycle can be restored by epigenetic modification, including reprogramming the tumor-associated immunity and eliciting an immune response. Epigenetic combination therapies may be optimally integrated to enhance the response rates of PD-L1/PD-1 blockade.Image 1

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d1ca7b0479f6fea7a89a3e1eb06905c5Test
https://doi.org/10.1016/j.apsb.2019.09.006Test

المؤلفون: Yuanming Qi, Guodong Li, Hongfei Wang, Xinghua Sui, Yanfeng Gao, Guanyu Chen, Wanqiong Li, Wenjie Zhai, Xiuman Zhou

المصدر: Acta Pharmaceutica Sinica. B
Acta Pharmaceutica Sinica B, Vol 10, Iss 6, Pp 1047-1060 (2020)

مصطلحات موضوعية: Original article, T cell, medicine.medical_treatment, Cancer immunotherapy, 03 medical and health sciences, 0302 clinical medicine, LAG-3, medicine, Cytotoxic T cell, MTT assay, General Pharmacology, Toxicology and Pharmaceutics, 030304 developmental biology, 0303 health sciences, biology, Chemistry, lcsh:RM1-950, FOXP3, Immune checkpoint, medicine.anatomical_structure, lcsh:Therapeutics. Pharmacology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Cyclic peptide, Phage display, Antibody, CD8+ T cell, CD8, Immune checkpoint blockade

الوصف: PD-1 and CTLA-4 antibodies offer great hope for cancer immunotherapy. However, many patients are incapable of responding to PD-1 and CTLA-4 blockade and show low response rates due to insufficient immune activation. The combination of checkpoint blockers has been proposed to increase the response rates. Besides, antibody drugs have disadvantages such as inclined to cause immune-related adverse events and infiltration problems. In this study, we developed a cyclic peptide C25 by using Ph.D.-C7C phage display technology targeting LAG-3. As a result, C25 showed a relative high affinity with human LAG-3 protein and could effectively interfere the binding between LAG-3 and HLA-DR (MHC-II). Additionally, C25 could significantly stimulate CD8+ T cell activation in human PBMCs. The results also demonstrated that C25 could inhibit tumor growth of CT26, B16 and B16-OVA bearing mice, and the infiltration of CD8+ T cells was significantly increased while FOXP3+ Tregs significantly decreased in the tumor site. Furthermore, the secretion of IFN-γ by CD8+ T cells in spleen, draining lymph nodes and especially in the tumors was promoted. Simultaneously, we exploited T cells depletion models to study the anti-tumor mechanisms for C25 peptide, and the results combined with MTT assay confirmed that C25 exerted anti-tumor effects via CD8+ T cells but not direct killing. In conclusion, cyclic peptide C25 provides a rationale for targeting the immune checkpoint, by blockade of LAG-3/HLA-DR interaction in order to enhance anti-tumor immunity, and C25 may provide an alternative for cancer immunotherapy besides antibody drugs.
Graphical abstract Cyclic peptide C25 targeting LAG-3 was developed by phage display bio-panning. C25 binds to LAG-3 and is capable of preventing the binding of LAG-3 to HLA-DR. C25 exhibits significant anti-tumor activity dependent on CD8+ T cells activation. Surprisingly, it can also lead to the reduction of Tregs in tumor microenvironment.Image 1

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5d5371ad86abe5d20d04e1887e733eb2Test
http://europepmc.org/articles/PMC7332792Test