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NK cell immune checkpoint blockade

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https://read.qxmd.com/read/30765392/a-variant-of-a-killer-cell-immunoglobulin-like-receptor-is-associated-with-resistance-to-pd-1-blockade-in-lung-cancer
#1
Marcel P Trefny, Sacha I Rothschild, Franziska Uhlenbrock, Dietmar Rieder, Benjamin Kasenda, Michal A Stanczak, Fiamma Berner, Abhishek S Kashyap, Monika Kaiser, Petra Herzig, Severin Poechtrager, Daniela S Thommen, Florian Geier, Spasenija Savic, Philip Jermann, Ilaria Alborelli, Stefan Schaub, Frank Stenner, Martin Früh, Zlatko Trajanoski, Lukas Flatz, Kirsten D Mertz, Alfred Zippelius, Heinz Läubli
PURPOSE: PD-(L)1 blocking antibodies have clinical activity in metastatic non-small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade.Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells were collected from 35 NSCLC patients receiving nivolumab monotherapy...
February 14, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://read.qxmd.com/read/30746216/programmed-cell-death-protein-1-programmed-death-ligand-1-blockade-enhances-the-antitumor-efficacy-of-adoptive-cell-therapy-against-non-small-cell-lung-cancer
#2
Jingyi Chen, Yusong Chen, Fenglan Feng, Cheng Chen, Haikang Zeng, Shuai Wen, Xin Xu, Jianxing He, Jin Li
Background: Cytokine-induced killer (CIK) cells and natural killer (NK) cells are employed by two different approaches to adoptive cell immunotherapy for cancer. It has been reported that adoptive cell immunotherapy could prolong the overall survival (OS) of advanced cancer patients. The introduction of agents that induce immune checkpoint blockades has improved the efficacy of immune-mediated therapy for metastatic cancers. However, the effects of combining a checkpoint inhibitor with CIK cells or NK cells to target non-small cell lung cancer (NSCLC)remain unknown...
December 2018: Journal of Thoracic Disease
https://read.qxmd.com/read/30745366/immune-profiling-and-quantitative-analysis-decipher-the-clinical-role-of-immune-checkpoint-expression-in-the-tumor-immune-microenvironment-of-dlbcl
#3
Ziju Xu-Monette, Min Xiao, Qingyan Au, Raghav Padmanabhan, Bing Xu, Nicholas Hoe, Sandra Rodriguez-Perales, Raul Torres-Ruiz, Ganiraju Manyam, Carlo Visco, Yi Miao, Xiaohong Tan, Hongwei Zhang, Alexandar Tzankov, Jing Wang, Karen Dybkaer, Wayne Tam, Hua You, Govind Bhagat, Eric D Hsi, Maurilio Ponzoni, Andrés J M Ferreri, Michael B Møller, Miguel A Piris, J Han van Krieken, Jane N Winter, Jason R Westin, Lan V Pham, L Jeffrey Medeiros, George Z Rassidakis, Yong Li, Gordon J Freeman, Ken H Young
PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for twelve types of cancer and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants...
February 11, 2019: Cancer Immunology Research
https://read.qxmd.com/read/30718505/virus-specific-memory-t-cells-populate-tumors-and-can-be-repurposed-for-tumor-immunotherapy
#4
Pamela C Rosato, Sathi Wijeyesinghe, J Michael Stolley, Christine E Nelson, Rachel L Davis, Luke S Manlove, Christopher A Pennell, Bruce R Blazar, Clark C Chen, Melissa A Geller, Vaiva Vezys, David Masopust
The immunosuppressive tumor microenvironment limits the success of current immunotherapies. The host retains memory T cells specific for previous infections throughout the entire body that are capable of executing potent and immediate immunostimulatory functions. Here we show that virus-specific memory T cells extend their surveillance to mouse and human tumors. Reactivating these antiviral T cells can arrest growth of checkpoint blockade-resistant and poorly immunogenic tumors in mice after injecting adjuvant-free non-replicating viral peptides into tumors...
February 4, 2019: Nature Communications
https://read.qxmd.com/read/30693544/an-efficient-combination-immunotherapy-for-primary-liver-cancer-by-harmonized-activation-of-innate-and-adaptive-immunity
#5
Liang Wen, Bing Xin, Panyisha Wu, Chia-Hao Lin, Chuanhui Peng, Gaowei Wang, Jin Lee, Li-Fan Lu, Gen-Sheng Feng
Immunotherapy with checkpoint inhibitors for liver cancer, while active in many clinical trials worldwide, may have uncertain outcomes due to the unique immunotolerant microenvironment of the liver. In previous experiments, we unexpectedly identified a robust liver tumor-preventive effect of a synthetic double-stranded RNA (dsRNA) polyinosinic-polycytidylic acid (polyIC) in mice. Herein we further demonstrate that polyIC given at the pre-cancer stage effectively prevented liver tumorigenesis by activating NK cells, macrophages and some T cell subsets; no inhibitory effect was observed on tumor progression if injected after tumor initiation...
January 28, 2019: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://read.qxmd.com/read/30683910/frequent-structural-variations-involving-programmed-death-ligands-in-epstein-barr-virus-associated-lymphomas
#6
Keisuke Kataoka, Hiroaki Miyoshi, Seiji Sakata, Akito Dobashi, Lucile Couronné, Yasunori Kogure, Yasuharu Sato, Kenji Nishida, Yuka Gion, Yuichi Shiraishi, Hiroko Tanaka, Kenichi Chiba, Yosaku Watatani, Nobuyuki Kakiuchi, Yusuke Shiozawa, Tetsuichi Yoshizato, Kenichi Yoshida, Hideki Makishima, Masashi Sanada, Masahiro Onozawa, Takanori Teshima, Yumiko Yoshiki, Tadao Ishida, Kenshi Suzuki, Kazuyuki Shimada, Akihiro Tomita, Motohiro Kato, Yasunori Ota, Koji Izutsu, Ayako Demachi-Okamura, Yoshiki Akatsuka, Satoru Miyano, Tadashi Yoshino, Philippe Gaulard, Olivier Hermine, Kengo Takeuchi, Koichi Ohshima, Seishi Ogawa
Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%)...
January 25, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://read.qxmd.com/read/30659055/mouse-pvrig-has-cd8-t-cell-specific-coinhibitory-functions-and-dampens-antitumor-immunity
#7
Benjamin Murter, Xiaoyu Pan, Eran Ophir, Zoya Alteber, Meir Azulay, Rupashree Sen, Ofer Levy, Liat Dassa, Ilan Vaknin, Tal Fridman-Kfir, Ran Salomon, Achinoam Ravet, Ada Tam, Doron Levin, Yakir Vaknin, Evgeny Tatirovsky, Arthur Machlenkin, Drew Pardoll, Sudipto Ganguly
A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor-related immunoglobulin domain protein (PVRIG) acts as a coinhibitory receptor in mice. Murine PVRIG interacted weakly with poliovirus receptor (PVR) but bound poliovirus receptor-like 2 (PVRL2) strongly, making the latter its principal ligand. As in humans, murine NK and NKT cells constitutively expressed PVRIG...
January 18, 2019: Cancer Immunology Research
https://read.qxmd.com/read/30651291/il2-anti-il2-complex-combined-with-ctla-4-but-not-pd-1-blockade-rescues-antitumor-nk-cell-function-by-regulatory-t-cell-modulation
#8
Pamela Caudana, Nicolas Núñez, Philippe DelaRochere, Anaïs Pinto, Jordan Denizeau, Ruby Alonso, Leticia Niborski, Olivier Lantz, Christine Sedlik, Eliane Piaggio
High-dose IL2 immunotherapy can induce long-lasting cancer regression but is toxic and insufficiently efficacious. Improvements are obtained with IL2/anti-IL2 complexes (IL2Cx) which re-direct IL2 action to CD8+ T and NK cells. Here, we evaluated the efficacy of combining IL2Cx with blockade of inhibitory immune pathways. In an autochthonous lung adenocarcinoma model, we show that the IL2Cx/anti-PD-1 combination increases CD8+ T-cell infiltration of the lung and controls tumor growth. In the B16-OVA model, which is resistant to checkpoint inhibition, combination of IL2Cx with PD-1 or CTLA-4 pathway blockade reverses that resistance...
January 16, 2019: Cancer Immunology Research
https://read.qxmd.com/read/30639819/monitoring-tigit-dnam-1-and-pvr-pvrl2-immune-checkpoint-s-expression-levels-in-allogeneic-stem-cell-transplantation-for-acute-myeloid-leukemia
#9
Norimichi Hattori, Yukiko Kawaguchi, Yohei Sasaki, Shotaro Shimada, So Murai, Maasa Abe, Yuta Baba, Megumi Watanuki, Shun Fujiwara, Nana Arai, Nobuyuki Kabasawa, Hiroyuki Tsukamoto, Yui Uto, Kouji Yanagisawa, Bungo Saito, Hiroshi Harada, Tsuyoshi Nakamaki
After allogeneic stem cell transplantation (alloSCT), several immune checkpoints play an important role in the antileukemic immune response in the bone marrow (BM) microenvironment. However, immune checkpoint expression levels in the BM have not been reported after alloSCT in patients with acute myeloid leukemia (AML). We investigated the clinical impact of immune checkpoint expression in BM samples following alloSCT for AML. Higher expression of T-cell immunoreceptor with Ig and ITIM domains (TIGIT) was associated with a decreased incidence of acute graft-versus-host disease (p = 0...
January 10, 2019: Biology of Blood and Marrow Transplantation
https://read.qxmd.com/read/30582788/nanoscale-reduced-graphene-oxide-mediated-photothermal-therapy-together-with-ido-inhibition-and-pd-l1-blockade-synergistically-promote-antitumor-immunity
#10
Mengmeng Yan, Yijia Liu, Xianghui Zhu, Xiaoli Wang, Lanxia Liu, Hongfan Sun, Chun Wang, Deling Kong, Guilei Ma
Despite the potential efficacy of immune checkpoint blockade for effective treatment of cancer, this therapeutic modality is not generally curative and only a fraction of patients respond. Combination approaches provide strategies to target multiple antitumor immune pathways to induce synergistic antitumor immunity. Here, a multi-combination immunotherapy including photothermal therapy (PTT), indoleamine-2,3-dioxygenase (IDO) inhibition and programmed cell death-ligand 1 (PD-L1) blockade is introduced for inducing synergistic antitumor immunity...
December 24, 2018: ACS Applied Materials & Interfaces
https://read.qxmd.com/read/30555485/intrinsic-expression-of-immune-checkpoint-molecule-tigit-could-help-tumor-growth-in-vivo-by-suppressing-the-function-of-nk-and-cd8-t-cells
#11
Xiu-Man Zhou, Wan-Qiong Li, Ya-Hong Wu, Lu Han, Xin-Guang Cao, Xuan-Ming Yang, Hong-Fei Wang, Wen-Shan Zhao, Wen-Jie Zhai, Yuan-Ming Qi, Yan-Feng Gao
TIGIT, an immune checkpoint molecule widely expressed on NK cells, activated T cells and Tregs, has been involved in delivering inhibitory signals through the interaction with PVR. The blockade of TIGIT/PVR interaction is a promising approach in cancer immunotherapy. Here, we unexpectedly discovered the expression of TIGIT in murine tumor cells. To elucidate the mechanism of such intrinsic expression, TIGIT knockout murine colorectal CT26 and MC38 cell lines were generated by using CRISPR/Cas9 system. Although TIGIT knockout showed no effects on proliferation and colony formation of tumor cells in vitro , the tumor growth in mice was considerably inhibited...
2018: Frontiers in Immunology
https://read.qxmd.com/read/30550791/organoid-modeling-of-the-tumor-immune-microenvironment
#12
James T Neal, Xingnan Li, Junjie Zhu, Valeria Giangarra, Caitlin L Grzeskowiak, Jihang Ju, Iris H Liu, Shin-Heng Chiou, Ameen A Salahudeen, Amber R Smith, Brian C Deutsch, Lillian Liao, Allison J Zemek, Fan Zhao, Kasper Karlsson, Liora M Schultz, Thomas J Metzner, Lincoln D Nadauld, Yuen-Yi Tseng, Sahar Alkhairy, Coyin Oh, Paula Keskula, Daniel Mendoza-Villanueva, Francisco M De La Vega, Pamela L Kunz, Joseph C Liao, John T Leppert, John B Sunwoo, Chiara Sabatti, Jesse S Boehm, William C Hahn, Grace X Y Zheng, Mark M Davis, Calvin J Kuo
In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages)...
December 13, 2018: Cell
https://read.qxmd.com/read/30513816/targeting-adenosine-receptor-signaling-in-cancer-immunotherapy
#13
REVIEW
Kevin Sek, Christina Mølck, Gregory D Stewart, Lev Kats, Phillip K Darcy, Paul A Beavis
The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of 'checkpoint blockade' and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient's own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function...
December 2, 2018: International Journal of Molecular Sciences
https://read.qxmd.com/read/30503213/anti-nkg2a-mab-is-a-checkpoint-inhibitor-that-promotes-anti-tumor-immunity-by-unleashing-both-t-and-nk-cells
#14
Pascale André, Caroline Denis, Caroline Soulas, Clarisse Bourbon-Caillet, Julie Lopez, Thomas Arnoux, Mathieu Bléry, Cécile Bonnafous, Laurent Gauthier, Ariane Morel, Benjamin Rossi, Romain Remark, Violette Breso, Elodie Bonnet, Guillaume Habif, Sophie Guia, Ana Ines Lalanne, Caroline Hoffmann, Olivier Lantz, Jérôme Fayette, Agnès Boyer-Chammard, Robert Zerbib, Pierre Dodion, Hormas Ghadially, Maria Jure-Kunkel, Yannis Morel, Ronald Herbst, Emilie Narni-Mancinelli, Roger B Cohen, Eric Vivier
Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells...
November 13, 2018: Cell
https://read.qxmd.com/read/30503208/nkg2a-blockade-potentiates-cd8-t-cell-immunity-induced-by-cancer-vaccines
#15
Nadine van Montfoort, Linda Borst, Michael J Korrer, Marjolein Sluijter, Koen A Marijt, Saskia J Santegoets, Vanessa J van Ham, Ilina Ehsan, Pornpimol Charoentong, Pascale André, Nicolai Wagtmann, Marij J P Welters, Young J Kim, Sytse J Piersma, Sjoerd H van der Burg, Thorbald van Hall
Tumor-infiltrating CD8 T cells were found to frequently express the inhibitory receptor NKG2A, particularly in immune-reactive environments and after therapeutic cancer vaccination. High-dimensional cluster analysis demonstrated that NKG2A marks a unique immune effector subset preferentially co-expressing the tissue-resident CD103 molecule, but not immune checkpoint inhibitors. To examine whether NKG2A represented an adaptive resistance mechanism to cancer vaccination, we blocked the receptor with an antibody and knocked out its ligand Qa-1b , the conserved ortholog of HLA-E, in four mouse tumor models...
November 7, 2018: Cell
https://read.qxmd.com/read/30411378/human-cd96-correlates-to-nk-cell-exhaustion-and-predicts-the-prognosis-of-human-hepatocellular-carcinoma
#16
Haoyu Sun, Qiang Huang, Mei Huang, Hao Wen, Renyong Lin, Meijuan Zheng, Kun Qu, Kun Li, Haiming Wei, Weihua Xiao, Rui Sun, Zhigang Tian, Cheng Sun
Immune checkpoint blockade has become a promising therapeutic approach to reverse immune cell exhaustion. Co-inhibitory CD96 and TIGIT, together with co-stimulatory CD226, bind to common ligand CD155. The balancing between three receptors fine tunes the immune responses against tumors. In this study, we investigated the expression of CD96, TIGIT and CD226 in 55 fresh human hepatocellular carcinoma (HCC) samples, 236 paraffin-embedded HCC samples, and 20 normal human livers. The cumulative percentage, absolute count, and MFI of CD96+ NK cells are significantly increased in the intratumoral tissues of HCC, and break the balance between three receptors...
November 8, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://read.qxmd.com/read/30352860/nk-cells-respond-to-checkpoint-blockade
#17
(no author information available yet)
A recent study suggests that natural killer (NK) cells may play an important role in antitumor response to immune checkpoint inhibitors. Researchers used mouse models to show that NK cells respond to PD-1 and PD-L1 inhibitors, information that could be used to develop immunotherapies that tap NK cells to combat cancer.
October 23, 2018: Cancer Discovery
https://read.qxmd.com/read/30294328/avelumab-an-igg1-anti-pd-l1-immune-checkpoint-inhibitor-triggers-nk-cell-mediated-cytotoxicity-and-cytokine-production-against-triple-negative-breast-cancer-cells
#18
Estefanía Paula Juliá, Analía Amante, María Betina Pampena, José Mordoh, Estrella Mariel Levy
The standard treatment for Triple Negative Breast Cancer (TNBC) patients is cytotoxic chemotherapy, but it is restricted since the duration of response is usually short. Blocking the PD-1/PD-L1 pathway through monoclonal antibodies (mAbs) appears to be a promising therapeutic strategy for TNBC patients. Avelumab is a human IgG1 anti-PD-L1 mAb being tested in clinical trials that may also trigger antibody-dependent cell-mediated cytotoxicity (ADCC) against cancer cells as an additional antitumor activity. In the present work, we studied in vitro Avelumab-mediated ADCC against a panel of TNBC cells with different PD-L1 expression using peripheral blood mononuclear cells (PBMC) or purified NK cells from healthy donors...
2018: Frontiers in Immunology
https://read.qxmd.com/read/30290143/immune-checkpoint-inhibition-overcomes-adcp-induced-immunosuppression-by-macrophages
#19
Shicheng Su, Jinghua Zhao, Yue Xing, Xiaoqian Zhang, Jiang Liu, Qian Ouyang, Jianing Chen, Fengxi Su, Qiang Liu, Erwei Song
Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression...
October 4, 2018: Cell
https://read.qxmd.com/read/30282672/pd-l1-mediates-dysfunction-in-activated-pd-1-nk-cells-in-head-and-neck-cancer-patients
#20
Fernando Concha-Benavente, Benjamin Kansy, Jessica Moskovitz, Jennifer Moy, Uma Chandran, Robert L Ferris
Inhibitory immune-checkpoint receptors (ICRs), including programmed death 1 (PD-1), have been characterized as exhaustion markers on T cells that infiltrate the tumor microenvironment (TME) of many cancer types, including head and neck cancer (HNC). However, expression and function of ICRs, including PD-1, on natural killer (NK) cells remains less defined. NK cells are innate immune effector cells that lyse epidermal growth factor receptor-overexpressing HNC cells via cetuximab-mediated antibody-dependent cytotoxicity...
October 3, 2018: Cancer Immunology Research
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