المؤلفون: Ryusaku Matsumoto, Masaaki Yamamoto, Genzo Iguchi, Shin Urai, Hidenori Fukuoka, Wataru Ogawa, Kentaro Suda, Hiroki Shichi, Keitaro Kanie, Yutaka Takahashi, Hironori Bando, Yasunori Fujita

المصدر: Cancer Immunology, Immunotherapy

مصطلحات موضوعية: Male, Cancer Research, Pro-Opiomelanocortin, Paraneoplastic Syndromes, Programmed Cell Death 1 Receptor, Autoimmunity, Hypopituitarism, Immune checkpoint inhibitor, medicine.disease_cause, B7-H1 Antigen, Mice, 0302 clinical medicine, Neoplasms, Immunology and Allergy, CTLA-4 Antigen, Corticotrophs, Immune Checkpoint Inhibitors, Aged, 80 and over, biology, Middle Aged, Oncology, 030220 oncology & carcinogenesis, Paraneoplastic syndrome, Female, Original Article, Immunotherapy, Antibody, hormones, hormone substitutes, and hormone antagonists, Adult, endocrine system, Hypophysitis, Immunology, 030209 endocrinology & metabolism, Adrenocorticotropic hormone, 03 medical and health sciences, Antigen, medicine, Animals, Humans, Aged, Retrospective Studies, business.industry, medicine.disease, biology.protein, Ectopic expression, Corticotropic cell, business, Adrenal Insufficiency

الوصف: Background Immune checkpoint inhibitors (ICIs) as a cancer immunotherapy have emerged as a treatment for multiple advanced cancer types. Because of enhanced immune responses, immune-related adverse events (irAEs), including endocrinopathies such as hypophysitis, have been associated with the use of ICIs. Most underlying mechanisms of ICI-related hypophysitis remain unclear, especially for programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors. We hypothesized that ICI-related hypophysitis is associated with paraneoplastic syndrome caused by ectopic expression of pituitary-specific antigens. Methods Twenty consecutive patients with ICI-related hypophysitis between 2017 and 2019 at Kobe University Hospital were retrospectively analyzed. Circulating anti-pituitary antibodies were detected using immunofluorescence staining and immunoblotting. Ectopic expression of pituitary autoantigens in tumor specimens was also examined. Results Eighteen patients were treated with PD-1/PD-L1 inhibitors, and two were treated with a combination of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1 inhibitors. All patients showed adrenocorticotropic hormone (ACTH) deficiency and additionally, three showed thyroid-stimulating hormone (TSH) deficiency, and one showed gonadotropin-releasing hormone (GnRH) deficiency. Among these patients, three exhibited anti-pituitary antibodies, two with anti-corticotroph antibody and one with anti-somatotroph antibody. Interestingly, the anti-corticotroph antibody recognized proopiomelanocortin (POMC) and those two patients exhibited ectopic ACTH expression in the tumor, while the patients without anti-corticotroph antibody did not. Conclusions We demonstrated 10% of PD-1/PD-L1 inhibitors-related hypophysitis were associated with the autoimmunity against corticotrophs and maybe caused as a form of paraneoplastic syndrome, in which ectopic expression of ACTH in the tumor was observed. It is also suggested that the pathophysiology is heterogenous in ICI-related hypophysitis.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3acc181a81511e7fe6b828ea748faa32Test
https://hdl.handle.net/20.500.14094/90008773Test

المؤلفون: Tevriz Dilan Demir, Ayca Sayi-Yazgan, Umit Ince, Sinem Oktem-Okullu, Nogayhan Seymen, Arzu Tiftikçi, Nurdan Tözün, Ugur Sezerman, Sawsan Sudqi Said, Fatma Tokat, Elif Merve Aydın, Bahattin Çiçek

المصدر: Immunology Letters. 239:1-11

مصطلحات موضوعية: Adult, CD4-Positive T-Lymphocytes, Male, Virulence Factors, Biopsy, Programmed Cell Death 1 Receptor, Immunology, Virulence, B7-H1 Antigen, Helicobacter Infections, Young Adult, Bacterial Proteins, Stomach Neoplasms, Immunopathology, PD-L1, Biomarkers, Tumor, medicine, Humans, Immunology and Allergy, CagA, Stomach Ulcer, Aged, Aged, 80 and over, Helicobacter pylori, biology, FOXP3, Cancer, Middle Aged, medicine.disease, biology.organism_classification, digestive system diseases, Gastric Mucosa, Gastritis, Disease Progression, biology.protein, Cancer research, Female, medicine.symptom, Signal Transduction

الوصف: Background The progression to gastric cancer has been linked to chronic infection with Helicobacter pylori (H. pylori). Immune checkpoint inhibitors (programmed cell death -1, PD-1; programmed cell death –ligand 1, PD-L1) have a role in cancer immune escape. The relationship between H. pylori virulence factors with PD-1, PD-L1 T helper 1 (Th1), T helper 17 (Th17), and regulatory T cell (Treg) response genes, has not been thoroughly investigated in the development of gastric cancer. Therefore, we evaluated how H. pylori virulence factors influence the expression levels of immune-related genes in the development of gastric immunopathology. Methods A total of 92 gastric tissues of normal controls and patients with gastritis, gastric ulcer, and gastric cancer were examined for the expression of immune-checkpoint inhibitor genes (PD-1 PD-L1), Th1 (interferon- γ, IFN-γ), Th17 (interleukin- 17, IL-17, Retinoic-acid-receptor- related orphan nuclear receptor gamma t, RORγ-t), and Treg (Forkhead box P3, FOXP3) response genes with quantitative real-time PCR (qRT-PCR). Furthermore, correlation of H. pylori virulence factors’ (cytotoxin-associated gene A, cagA; vacuolating cytotoxin gene A, vacA (s1,s2,m1,m2); blood group antigen-binding adhesin gene A, babA, duodenal ulcer promoting gene A, dupA; the putative neuraminyllactose-binding hemagglutinin homolog, hpaA; neutrophil-activating protein A napA; outer inflammatory protein A, oipA; urease A, ureA; and urease B, ureB) genotypes with a degree of inflammation and density of H. pylori were investigated. Next, the relationship between H. pylori virulence factors and immune-checkpoint inhibitor genes, and T-cell response genes was evaluated. Eventually, a decision tree model was developed to determine the clinical outcome of patients using expression data. Results The intensity of PD-1 and PD-L1 mRNA expression was increased significantly in gastric tissue of patients with gastric ulcer (PD-1: 2.3 fold, p=0.01; PD-L1: 2.1 fold, p=0.004), and gastric cancer (PD-1: 2 fold, p= 0.04; PD-L1: 1.8 fold, p=0.05) compared with control subjects. Also, PD-1: PD-L1 expression was significantly higher in patients with gastritis, who were infected with a marked density of H. pylori compared with its mildly infected counterparts. Furthermore, a novel negative correlation was found between PD-1 (r= -0.43) and PD-L1 (r= -0.42) with FOXP3 in patients with gastritis. CagA-positive H. pylori strain's negative association with PD-L1 expression (r=-0.34) was detected in patients with gastritis. Interestingly, PD-1 mRNA expression correlated positively with vacA s2/m2, in gastritis (r=0.43) and ulcer (r=0.43) patients. Furthermore, PD-1: PDL1 expression negatively correlated with vacA m1/m2 (r=-0.43 for PD-1; r=-0.38 for PD-L1) in gastritis patients. Moreover, an inverse correlation of PDL1 was present with vacA m1 (r=0.52) and vacA s1/m1 (r=0.46) versus vacA m2 (r=-0.44) and vacA m1 (r=0.52) and vacA s1/m2 (r=-0.14) in ulcer patients, respectively. Also, a correlation of vacA m2 (r=-0.47) and vacA s1/s2 (r= 0.45) with PD-1 was detected in ulcer patients. In addition, a novel negative correlation between FOXP3 mRNA levels and napA was shown in patients with gastritis and ulcer (r=-0.59). Finally, a computer-based model that was developed showed that knowing the expression levels of PD-L1, RORγ-t, and vacA s1/m2 would be useful to detect the clinical outcome of a patient. Conclusion Our results suggested that PD-1:PD-L1 immune checkpoint inhibitors were increased in gastric pre-cancerous lesions that progress to gastric cancer. Herein, we report the relationship between H. pylori virulence factors and expression of host immune checkpoint inhibitors for diagnostic prediction of gastric malignancies using computer-based models.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fb3a70d385c0111e337afecbe6a6acf2Test
https://doi.org/10.1016/j.imlet.2021.06.009Test

المؤلفون: Eloise Vandebeuque, Virginie Gonzalez, Grégory Marin, Yannick Allanore, Claire Daien, Sonia Pezet, Jérôme Avouac, Gaël Mouterde, Cindy Orvain

المصدر: Arthritis & Rheumatology. 73:1579-1588

مصطلحات موضوعية: Adult, Male, Angiogenesis, Immunology, SEMA4D, Inflammation, Semaphorins, Arthritis, Rheumatoid, Rheumatology, Semaphorin, Neuropilin 1, Humans, Immunology and Allergy, Medicine, Receptor, Aged, Neovascularization, Pathologic, business.industry, Gene Expression Profiling, Synovial Membrane, Endothelial Cells, SEMA3A, Middle Aged, Cancer research, Female, Tumor necrosis factor alpha, medicine.symptom, business

الوصف: OBJECTIVE To study the potential role of semaphorins in the pathogenesis of rheumatoid arthritis (RA). METHODS Microarray experiments were performed on Affymetrix GeneChip Human Exon 1.0 ST arrays in RA endothelial cells (ECs) and control ECs derived from circulating progenitors. Expression of class 3 and class 4 semaphorins and their receptors in the serum of RA patients and healthy controls was assessed by immunohistochemical analysis in synovial tissue and by enzyme-linked immunosorbent assay. RESULTS Microarray analysis revealed differential expression of class 3 and class 4 semaphorins and their receptors in RA ECs. Semaphorin 4A (SEMA4A), plexin D1, and neuropilin 1 messenger RNA (mRNA) levels were markedly increased in RA ECs by 1.75-, 2.21-, and 1.68-fold, respectively. Stimulation with tumor necrosis factor (TNF) led to a 2-fold increase in SEMA4A mRNA levels in RA ECs, and deficient SEMA4A expression modified RA EC angiogenic properties. Class 3 and class 4 semaphorins as well as their receptors were overexpressed in RA synovial tissue. A respective 1.30-fold increase and 1.54-fold increase in SEMA4A and SEMA3E, as well as a 24% decrease in SEMA3A, was observed in the serum of RA patients. Serum levels of SEMA4A, SEMA4D, and SEMA3A correlated with levels of inflammation and proangiogenic markers. In 2 independent cohorts of patients with low disease activity or with RA in remission, the presence of SEMA4A identified patients with residual disease activity. CONCLUSION Gene expression profiling of ECs identified class 3 and class 4 semaphorins as potential biomarkers and therapeutic candidates in RA, with confirmed overexpression in ECs, synovial vessels, and serum, and correlation with validated markers of inflammation and angiogenesis. Thus, semaphorins might be novel and appealing EC-derived inflammatory and proangiogenic targets in RA.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f7da3373e7f50966dd48371cd647c825Test
https://doi.org/10.1002/art.41701Test

المؤلفون: Salvatore Siena, Emilia Maria Cristina Mazza, Giulia Della Chiara, Chiara Godano, Nicola Zucchini, Valeria Ranzani, Stefania Oliveto, Paola Gruarin, Jens Geginat, Roberto Bosotti, Claudia D'Oria, Elena Carelli, Pierluigi Novellis, Saveria Mazzara, Ylenia Silvestri, Marco Passaro, Alessio Amatu, Marco Alloisio, Antonio Lanzavecchia, Stefano Biffo, Giorgia Alvisi, Federica Gervasoni, Maria Lucia Sarnicola, N. Mariani, Alberto Bardelli, Ramona Bason, Jolanda Brummelman, Mariangela Lorenzo, Giulia Veronesi, Emanuela Bonoldi, Massimiliano Pagani, Daniele Prati, Enrico Opocher, Lorenzo Drufuca, Martina Martinovic, Andrea Sartore-Bianchi, Sergio Abrignani, Alessandro Giani, Marco De Simone, Enrico Lugli, Chiara Cordiglieri, Serena Curti, Grazisa Rossetti, Valeria Bevilacqua, Andrea Pisani Ceretti, Raoul J. P. Bonnal

المساهمون: Bonnal, R. J. P., Rossetti, G., Lugli, E., De Simone, M., Gruarin, P., Brummelman, J., Drufuca, L., Passaro, M., Bason, R., Gervasoni, F., Della Chiara, G., D'Oria, C., Martinovic, M., Curti, S., Ranzani, V., Cordiglieri, C., Alvisi, G., Mazza, E. M. C., Oliveto, S., Silvestri, Y., Carelli, E., Mazzara, S., Bosotti, R., Sarnicola, M. L., Godano, C., Bevilacqua, V., Lorenzo, M., Siena, S., Bonoldi, E., Sartore-Bianchi, A., Amatu, A., Veronesi, G., Novellis, P., Alloisio, M., Giani, A., Zucchini, N., Opocher, E., Ceretti, A. P., Mariani, N., Biffo, S., Prati, D., Bardelli, A., Geginat, J., Lanzavecchia, A., Abrignani, S., Pagani, M.

المصدر: Nature Immunology, 22, 735-745
Nature Immunology, 22, 6, pp. 735-745

مصطلحات موضوعية: Male, 0301 basic medicine, Lung Neoplasms, T-Lymphocytes, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], medicine.medical_treatment, Programmed Cell Death 1 Receptor, Drug Resistance, Datasets as Topic, Kaplan-Meier Estimate, Granzymes, 0302 clinical medicine, Cancer immunotherapy, Single-cell analysis, 80 and over, Immunology and Allergy, RNA-Seq, Non-Small-Cell Lung, Immune Checkpoint Inhibitors, Adjuvant, Colectomy, Chitinases, Cell Differentiation, Forkhead Transcription Factors, Middle Aged, Flow Cytometry, Regulatory, Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Cell Proliferation, Chemotherapy, Adjuvant, Clonal Hematopoiesis, Colon, Colorectal Neoplasms, Disease Progression, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Primary Cell Culture, Single-Cell Analysis, T-Box Domain Proteins, T-Lymphocytes, Regulatory, Immunology, Biology, 03 medical and health sciences, Immune system, medicine, Chemotherapy, Neoplastic, Carcinoma, Immunotherapy, 030104 developmental biology, Gene Expression Regulation, Cell culture, Cancer research, Neoplasm, Granzyme K, Eomesodermin Homolog, Checkpoint Blockade Immunotherapy, 030215 immunology

الوصف: Regulatory T (Treg) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4+ T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3+ Treg and eomesodermin homolog (EOMES)+ type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES+ Tr1-like cells, but not Treg cells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES+ Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1–targeted immunotherapy. Collectively, these findings highlight the heterogeneity of Treg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy. Human primary and metastatic tumors harbor CD4+ Treg cells that can suppress antitumor immune responses. Bonnal et al. identify an intratumoral type 1 Treg-like CD4+ T cell subset that expresses the transcription factor EOMES, granzyme K and CHI3L2. This EOMES+ T cell subset correlates with disease progression but is responsive to PD-1 checkpoint blockade immunotherapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::73e12ccb9271b3892eb83d8342962f9dTest
https://doi.org/10.1038/s41590-021-00930-4Test

المؤلفون: Olivier Tredan, Romaine Mayet, Magali Morelle, Benoit You, François Parant, Marine Villard, Isabelle Ray-Coquard, Thomas Bachelot, Sébastien Viel, David Pérol, Emily Charrier, Yamila Rocca, Gwenaële Garin, Antoine Marçais, Laurie Besson, Pierre Heudel, Thierry Walzer, Benoîte Méry

المساهمون: Health System Analysis Laboratory (GATE), Université de Lyon

المصدر: Journal of Immunology
Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2021, 206 (10), pp.2265-2270. ⟨10.4049/jimmunol.2001215⟩

مصطلحات موضوعية: Adult, Immunology, Population, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Breast Neoplasms, mTORC1, Mechanistic Target of Rapamycin Complex 1, Biology, mTORC2, 03 medical and health sciences, 0302 clinical medicine, Immunophenotyping, medicine, Humans, Immunology and Allergy, Cytotoxic T cell, Everolimus, Prospective Studies, Neoplasm Metastasis, education, Mechanistic target of rapamycin, ComputingMilieux_MISCELLANEOUS, PI3K/AKT/mTOR pathway, Aged, Cell Proliferation, Aged, 80 and over, education.field_of_study, TOR Serine-Threonine Kinases, Cell Differentiation, Middle Aged, 3. Good health, Killer Cells, Natural, Treatment Outcome, medicine.anatomical_structure, Cancer research, biology.protein, Female, France, Follow-Up Studies, Signal Transduction, 030215 immunology

الوصف: NK cells are cytotoxic lymphocytes displaying strong antimetastatic activity. Mouse models and in vitro studies suggest a prominent role of the mechanistic target of rapamycin (mTOR) kinase in the control of NK cell homeostasis and antitumor functions. However, mTOR inhibitors are used as chemotherapies in several cancer settings. The impact of such treatments on patients’ NK cells is unknown. We thus performed immunophenotyping of circulating NK cells from metastatic breast cancer patients treated with the mTOR inhibitor everolimus over a three-month period. Everolimus treatment resulted in inhibition of mTORC1 activity in peripheral NK cells, whereas mTORC2 activity was preserved. NK cell homeostasis was profoundly altered with a contraction of the NK cell pool and an overall decrease in their maturation. Phenotype and function of the remaining NK cell population was less affected. This is, to our knowledge, the first in vivo characterization of the role of mTOR in human NK cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::86e180998e3e82cff3446bcec6dba5a5Test
https://doi.org/10.4049/jimmunol.2001215Test

المؤلفون: Kyoko Arai, Takao Kamai, Akinori Nukui, Minoru Kobayashi, Hideo Yuki, Takahiro Narimatsu, Yoshitatsu Fukabori, Toshiki Kijima, Ken-Ichiro Yoshida, Hideyuki Abe, Tsunehito Kambara, Hironori Betsunoh, Masahiro Yashi

المصدر: Cancer Immunology, Immunotherapy

مصطلحات موضوعية: Male, Cancer Research, Lymphocyte, Kidney, Nephroureterectomy, B7-H1 Antigen, Immune tolerance, 0302 clinical medicine, Tumor Microenvironment, Neutrophil-to-lymphocyte ratio (NLR), Immunology and Allergy, Stage (cooking), Aged, 80 and over, 0303 health sciences, Univariate analysis, Middle Aged, Prognosis, Kidney Neoplasms, Progression-Free Survival, Programmed cell death 1 ligand 1 (PD-L1), medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Upper tract urothelial carcinoma (UTUC), Disease Progression, Immunohistochemistry, Female, Original Article, Tumor-infiltrating lymphocyte (TIL), Adult, Immunology, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, medicine, Humans, Aged, Retrospective Studies, 030304 developmental biology, Carcinoma, Transitional Cell, Tumor microenvironment, Ureteral Neoplasms, Tumor-infiltrating lymphocytes, business.industry, Cancer, medicine.disease, Cancer research, Neoplasm Grading, Ureter, business, Follow-Up Studies

الوصف: Background Increased expression of programmed cell death 1 ligand 1 (PD-L1) by tumor cells is thought to be a mechanism through which solid cancers promote immune tolerance. However, the association between PD-L1 expression and the prognosis of upper urinary tract urothelial carcinoma (UTUC) remains unknown. Methods We examined immunohistochemical PD-L1 expression and the tumor-infiltrating lymphocyte density (TILD) in 79 patients with UTUC who underwent nephroureterectomy. We classified the tumors into four types based on the combination of PD-L1 expression and TILD, and studied the clinicopathological characteristics of these four tumor types. Results Elevated expression of PD-L1 by tumor cells and a higher TILD were associated with a worse histological grade, higher pT stage, and higher peripheral blood neutrophil-to-lymphocyte ratio. Elevated expression of PD-L1 by tumor cells, a higher TILD, and type I, III, or IV tumors with elevated expression of either PD-L1 or TILD showed a positive correlation with poorer differentiation and local invasion. These three variables were associated with shorter progression-free survival and overall survival in univariate analysis, but only the latter was an independent determinant according to multivariate analysis. The patients who had type II tumors with lower PD-L1 expression and a lower TILD showed more favorable survival than the other three groups. Conclusions These findings suggest that PD-L1 expression and TILs in the tumor microenvironment influence the progression of UTUC. Accordingly, it is important to understand the immunologic characteristics of the tumor microenvironment to develop more effective treatment strategies for this cancer.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2a089064114954a8996f5b69f009caefTest
https://doi.org/10.1007/s00262-020-02499-7Test

المؤلفون: William Rodin, Filip Ahlmanner, Elinor Bexe Lindskog, Yvonne Wettergren, Louis Szeponik, Kamil Kajetan Zajt, Marianne Quiding Järbrink, Patrik Sundström

المصدر: Cancer Immunology, Immunotherapy

مصطلحات موضوعية: Adult, Male, Cancer Research, Exhaustion, Immunology, Programmed Cell Death 1 Receptor, Tim-3, Lymphocyte Activation, Mucosal-Associated Invariant T Cells, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Immunity, Antigens, CD, Blocking antibody, PD-1, medicine, Tumor Microenvironment, Immunology and Allergy, Cytotoxic T cell, Humans, Secretion, Hepatitis A Virus Cellular Receptor 2, MAIT cell, 030304 developmental biology, Aged, Cell Proliferation, Aged, 80 and over, 0303 health sciences, Tumor microenvironment, CD39, medicine.diagnostic_test, Effector, Chemistry, Apyrase, Middle Aged, Colorectal cancer, In vitro, Phenotype, Oncology, Colonic Neoplasms, Cancer research, Cytokines, Original Article, Female, Biomarkers, 030215 immunology

الوصف: Mucosal-associated invariant T (MAIT) cells are unconventional T cells recognizing microbial metabolites, presented by the invariant MR1 protein. Upon activation, MAIT cells rapidly secrete cytokines and exert cytotoxic functions, and may thus be highly relevant also in tumor immunity. MAIT cells accumulate in colon tumors, but in contrast to other cytotoxic T cell subsets, their presence in tumors has been associated with worse patient outcome. Here we investigated if exhaustion may contribute to reduced anti-tumor immunity by MAIT cells. Freshly isolated lymphocytes from colon tumors, unaffected tissue and blood from the same patients were analyzed by flow cytometry to detect MAIT cells with effector functions that are relevant for tumor immunity, and their expression of inhibitory receptors and other exhaustion markers. Our studies show that MAIT cells with a PD-1highTim-3+CD39+ terminally exhausted phenotype and an increased proliferation accumulate in colon tumors. The exhausted MAIT cells have reduced polyfunctionality with regard to production of important anti-tumor effector molecules, and blocking antibodies to PD-1 partly improved activation of tumor-infiltrating MAIT cells in vitro. We conclude that the tumor microenvironment leads to exhaustion not only of conventional T cells, but also MAIT cells, and that checkpoint blockade therapy may be useful also to reinvigorate tumor-infiltrating MAIT cells. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-021-02939-y.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a8846e11fd7e69e73f9cd68dd02080acTest
http://europepmc.org/articles/PMC8571139Test

المؤلفون: Masanori Hayashi, Tetsuro Yamagishi, Chihaya Imai, Hajime Umezu, Takashi Ariizumi, Yudai Murayama, Akira Ogose, Naoki Oike, Hiroyuki Kawashima, Hiroshi Hatano, Naoto Endo

المصدر: Cancer Immunology, Immunotherapy

مصطلحات موضوعية: Male, Cancer Research, Pathology, medicine.medical_treatment, Liposarcomas, B7-H1 Antigen, 0302 clinical medicine, HLA Antigens, Tumor Microenvironment, Immunology and Allergy, Programmed death ligand 1, Aged, 80 and over, 0303 health sciences, Middle Aged, Prognosis, Immunohistochemistry, Liposarcoma, Myxoid, Progression-Free Survival, Oncology, 030220 oncology & carcinogenesis, Original Article, Female, Human leukocyte antigen I, Adult, medicine.medical_specialty, Adolescent, Tumor immune microenvironment, Immunology, Down-Regulation, Human leukocyte antigen, Liposarcoma, Pleomorphic Liposarcoma, 03 medical and health sciences, Young Adult, Lymphocytes, Tumor-Infiltrating, medicine, Humans, neoplasms, 030304 developmental biology, Aged, Myxoid liposarcoma, Tumor-infiltrating lymphocytes, business.industry, Macrophages, Histocompatibility Antigens Class I, Immunotherapy, medicine.disease, body regions, CD163+ macrophages, business, CD163

الوصف: The characteristics of the tumor immune microenvironment remains unclear in liposarcomas, and here we aimed to determine the prognostic impact of the tumor immune microenvironment across separate liposarcomas subtypes. A total of 70 liposarcoma patients with three subtypes: myxoid liposarcoma (n = 45), dedifferentiated liposarcoma (n = 17), and pleomorphic liposarcoma (n = 8) were enrolled. The presence of tumor infiltrating lymphocytes (CD4+ , CD8+ , FOXP3+ lymphocytes) and CD163+ macrophages and expression of HLA class I and PD-L1 were assessed by immunohistochemistry in the diagnostic samples; overall survival and progression-free survival were estimated from outcome data. For infiltrating lymphocytes and macrophages, dedifferentiated liposarcoma and pleomorphic liposarcoma patients had a significantly higher number than myxoid liposarcoma patients. While myxoid liposarcoma patients with a high number of macrophages were associated with worse overall and progression-free survival, dedifferentiated liposarcoma patients with high macrophage numbers showed a trend toward favorable prognosis. Expression of HLA class I was negative in 35 of 45 (77.8%) myxoid liposarcoma tumors, whereas all dedifferentiated liposarcoma and pleomorphic liposarcoma tumors expressed HLA class I. The subset of myxoid liposarcoma patients with high HLA class I expression had significantly poor overall and progression-free survival, while dedifferentiated liposarcoma patients with high HLA class I expression tended to have favorable outcomes. Only four of 17 (23.5%) dedifferentiated liposarcomas, two of eight (25%) pleomorphic liposarcomas, and no myxoid liposarcoma tumors expressed PD-L1. Our results demonstrate the unique immune microenvironment of myxoid liposarcomas compared to other subtypes of liposarcomas, suggesting that the approach for immunotherapy in liposarcomas should be based on subtype.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::80679c1ba2c44a0ce4ca344ffcd402aeTest
http://europepmc.org/articles/PMC8571150Test

المؤلفون: Mark-David Levin, Sanne H. Tonino, Sjoerd T.T. Schetters, Ester B. M. Remmerswaal, Adriaan D. Bins, Frederike J. Bemelman, Arnon P. Kater, Renate de Boer, Tom Hofland, Anne W. J. Martens, Eric Eldering, Jaco A. C. van Bruggen

المساهمون: Graduate School, AII - Cancer immunology, CCA - Cancer biology and immunology, AII - Amsterdam institute for Infection and Immunity, Experimental Immunology, Nephrology, APH - Aging & Later Life, Oncology, Clinical Haematology, CCA - Cancer Treatment and Quality of Life

المصدر: European Journal of Immunology
European journal of immunology, 51(3), 703-713. Wiley-VCH Verlag

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, Receptors, CXCR5, Chronic lymphocytic leukemia, PD-1 immunotherapy, Immunology, Programmed Cell Death 1 Receptor, Stimulation, CD8 T cells, Biology, CD8-Positive T-Lymphocytes, CXCR5, 03 medical and health sciences, Clinical, 0302 clinical medicine, PD‐1 immunotherapy, medicine, Immunology and Allergy, Cytotoxic T cell, Humans, Aged, Aged, 80 and over, Effector, Research Article|Clinical, Cell Differentiation, Middle Aged, immune checkpoint blockade, medicine.disease, Phenotype, Leukemia, Lymphocytic, Chronic, B-Cell, Immune checkpoint, 030104 developmental biology, Hematologic Neoplasms, Cancer research, Tumor immunology, Female, Lymph, Lymph Nodes, Immunologic Memory, 030215 immunology, Research Article

الوصف: Immune checkpoint blockade (ICB) has revolutionized cancer therapy, but varying response rates illustrate the need for biomarkers of response. Studies in mice have identified a subset of CD8 T cells that is essential for response to PD‐1 ICB. These CD8 T cells co‐express CXCR5, PD‐1 and Tcf1, and provide effector T cells upon PD‐1 ICB. It is unknown whether similar T cells play a role in PD‐1 ICB in humans. We studied human peripheral blood and lymph nodes (LNs) for the frequency, phenotype, and functionality of CXCR5+PD‐1+ CD8 T cells. We find that CXCR5+PD‐1+ CD8 T cells are memory‐like cells, express Tcf1, and lack expression of effector molecules. CXCR5+PD‐1+ CD8 T cells produce cytokines upon stimulation, but have limited proliferative capacity. We studied patients with hematologic malignancies with varying response rates to PD‐1 ICB. Specifically in chronic lymphocytic leukemia, in which PD‐1 ICB does not induce clinical responses, CXCR5+PD‐1+ CD8 T cells show loss of the memory phenotype and increased effector differentiation. In conclusion, we identified CXCR5+PD‐1+ CD8 T cells in human peripheral blood and LN, which could play a similar role during PD‐1 ICB. Future studies should analyze CXCR5+PD‐1+ CD8 T cells during PD‐1 ICB and their importance for therapeutic response.
CXCR5+PD‐1+ CD8 T cells respond to PD‐1 immune checkpoint blockade in mice. In healthy individuals, human CXCR5+PD‐1+ CD8 T cells have a similar memory phenotype and functionality. In CLL patients, where PD‐1 blockade does not induce therapeutic responses, CXCR5+PD‐1+ CD8 T cells show increased differentiation and altered functionality.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e54714957e1ea10a7a855bd9a6c9aaa0Test
https://doi.org/10.1002/eji.202048761Test

المؤلفون: Weibin Hou, Jian Huang, Kun Xia, Meihua Yang, Meng Yang, Junyu Chen, Bo Wang, Tianxin Lin, Wenlong Zhong, Bingkun Zhou, Xiaofei Wang, Hao Yu

المصدر: Cancer Immunology, Immunotherapy. 70:2657-2668

مصطلحات موضوعية: Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Immunology, Kaplan-Meier Estimate, CD8-Positive T-Lymphocytes, Nephroureterectomy, B7-H1 Antigen, Lymphocytes, Tumor-Infiltrating, PD-L1, Internal medicine, Biomarkers, Tumor, medicine, Humans, Immunology and Allergy, Stage (cooking), Survival rate, Aged, Neoplasm Staging, Aged, 80 and over, Urethral Neoplasms, biology, business.industry, Proportional hazards model, Cancer, Immunotherapy, Middle Aged, Nomogram, Prognosis, medicine.disease, Immunohistochemistry, Nomograms, ROC Curve, biology.protein, Female, Disease Susceptibility, business

الوصف: The expression status of programmed cell death-ligand 1/programmed cell death 1 (PD-L1/PD-1) and the infiltration of CD8+ T cells in tumor tissues are considered to be related to immunotherapy efficacy and patient prognosis. The purpose of this study is to clarify the prognostic value of the PD-L1/PD-1/CD8 axis, and to develop and validate a comprehensive scoring system based on multiple immune variables to predict cancer survival of upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). The immunohistochemical method was used to detect the expression of PD-L1, PD-1, and CD8 in cancer tissues of UTUC patients after RNU. Then, an immunoscore was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression model in the training cohort (n = 120), and it was verified in the validation cohort (n = 54). We found that infiltration of PD-L1+ immune cells (ICs), stromal PD-1+ tumor-infiltrating lymphocytes (TILs), and intratumoral CD8+ TILs was associated with poor overall survival (OS). The immunoscore based on the three immune variables further divided the patients into low- and high-risk groups, and there was a significant difference in the survival rate. A nomogram was constructed by combining tumor-node-metastasis (TNM) stage and immunoscore, and the area under the curve of the receiver-operating characteristic (ROC) (0.78) for predicting 5-year mortality was better than that of the TNM stage (0.70) and immunoscore (0.76). Our results show that the PD-L1/PD-1/CD8 axis-based classifier have potential clinical application to predict cancer survival of UTUC patients after RNU.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bec96ee69828b45ab4f3871ce3fc8c4bTest
https://doi.org/10.1007/s00262-020-02827-xTest