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NK cell immune checkpoint blockade

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
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
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
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
(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
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
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
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
Nayoung Kim, Hun Sik Kim
Among the most promising therapeutic modalities for cancer treatment is the blockade of immune checkpoint pathways, which are frequently co-opted by tumors as a major mechanism of immune escape. CTLA-4 and PD-1 are the representative examples, and their blockade by therapeutic antibodies leads to enhanced anti-tumor immunity with durable clinical responses, but only in a minority of patients. This has highlighted the need to identify and target additional immune checkpoints that can be exploited to further enhance immune responses to refractory cancers...
2018: Frontiers in Immunology
Joy Hsu, Jonathan J Hodgins, Malvika Marathe, Chris J Nicolai, Marie-Claude Bourgeois-Daigneault, Troy N Trevino, Camillia S Azimi, Amit K Scheer, Haley E Randolph, Thornton W Thompson, Lily Zhang, Alexandre Iannello, Nikhita Mathur, Karen E Jardine, Georgia A Kirn, John C Bell, Michael W McBurney, David H Raulet, Michele Ardolino
Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity...
October 1, 2018: Journal of Clinical Investigation
Tyler R McCaw, Troy D Randall, Rebecca C Arend
The impressive successes of immunotherapy have yet to be reliably translated to treatment of ovarian cancer, which may be a consequence of the unique barriers to T cell migration and tumor engagement in the peritoneal cavity and omentum. Epigenetic alterations contribute to establishment of these barriers and other mechanisms of immune subversion; therefore, epigenetic modifying agents represent an opportunity to mount effective antitumor immune responses by disrupting this finely tuned tumor epigenetic framework...
June 23, 2018: Translational Research: the Journal of Laboratory and Clinical Medicine
Martina Molgora, Domenico Supino, Domenico Mavilio, Angela Santoni, Lorenzo Moretta, Alberto Mantovani, Cecilia Garlanda
NK cells are innate lymphoid cells, which play a key role in the immune response to cancer and pathogens and participate in the shaping of adaptive immunity. NK cells engage in a complex bidirectional interaction with myelomonocytic cells. In particular, macrophages, dendritic cells and neutrophils promote differentiation and effector function of NK cells and, on the other hand, myelomonocytic cells express triggers of checkpoint blockade (eg PD-L1) and other immunosuppressive molecules, which negatively regulate NK cell function...
September 2018: Scandinavian Journal of Immunology
(no author information available yet)
Natural killer (NK) cell interactions with stimulatory dendritic cells (SDC) enhance immunotherapy.
September 2018: Cancer Discovery
Filippos Porichis, Meghan G Hart, Alexandra Massa, Holly L Everett, Antigoni Morou, Jonathan Richard, Nathalie Brassard, Maxime Veillette, Muska Hassan, Ngoc Le Ly, Jean-Pierre Routy, Gordon J Freeman, Mathieu Dubé, Andrés Finzi, Daniel E Kaufmann
Immune exhaustion is an important feature of chronic infections, such as HIV, and a barrier to effective immunity against cancer. This dysfunction is in part controlled by inhibitory immune checkpoints. Blockade of the PD-1 or IL-10 pathways can reinvigorate HIV-specific CD4 T cell function in vitro, as measured by cytokine secretion and proliferative responses upon Ag stimulation. However, whether this restoration of HIV-specific CD4 T cells can improve help to other cell subsets impaired in HIV infection remains to be determined...
August 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Juming Yan, Stacey Allen, Dipti Vijayan, Xian-Yang Li, Heidi Harjunpää, Kazuyoshi Takeda, Jing Liu, Daniel J Cua, Mark J Smyth, Michele W L Teng
Tumor-induced immunosuppression is mediated through various mechanisms including engagement of immune checkpoint receptors on effector cells, function of immunoregulatory cells such as regulatory T cells and myeloid-derived suppressor cells, and deployment of immunosuppressive cytokines such as TGFβ and IL10. IL23 is a cytokine that negatively affects antitumor immunity. In this study, we investigated whether IL23-deficient (IL23p19-/- ) and IL23R-deficient (IL23R-/- ) mice phenocopied each other, with respect to their tumor control...
August 2018: Cancer Immunology Research
Qing Zhang, Jiacheng Bi, Xiaodong Zheng, Yongyan Chen, Hua Wang, Wenyong Wu, Zhengguang Wang, Qiang Wu, Hui Peng, Haiming Wei, Rui Sun, Zhigang Tian
Checkpoint blockade enhances effector T cell function and has elicited long-term remission in a subset of patients with a broad spectrum of cancers. TIGIT is a checkpoint receptor thought to be involved in mediating T cell exhaustion in tumors; however, the relevance of TIGIT to the dysfunction of natural killer (NK) cells remains poorly understood. Here we found that TIGIT, but not the other checkpoint molecules CTLA-4 and PD-1, was associated with NK cell exhaustion in tumor-bearing mice and patients with colon cancer...
July 2018: Nature Immunology
Elizabeth Ahern, Heidi Harjunpää, Jake S O'Donnell, Stacey Allen, William C Dougall, Michele W L Teng, Mark J Smyth
Receptor activator of NF-κB ligand (RANKL) and its receptor RANK, are members of the tumor necrosis factor and receptor superfamilies, respectively. Antibodies targeting RANKL have recently been evaluated in combination with anti-CTLA4 in case reports of human melanoma and mouse models of cancer. However, the efficacy of anti-RANKL in combination with antibodies targeting other immune checkpoint receptors such as PD1 has not been reported. In this study, we demonstrated that blockade of RANKL improves anti-metastatic activity of antibodies targeting PD1/PD-L1 and improves subcutaneous growth suppression in mouse models of melanoma, prostate and colon cancer...
2018: Oncoimmunology
Masood Sadaat, Sekwon Jang
BACKGROUND: Hemophagocytic Lymphohistiocytosis (HLH), a rare but potentially fatal syndrome of immune hyperactivation, may be an under-recognized immune-related adverse event (irAE). Unlike other irAEs, HLH triggered by immune checkpoint blockade is not well described; no particular diagnostic guidelines and treatment regimens exist. The HLH-2004 criteria remain as the common diagnostic guide. For the treatment of HLH, various combinations of chemotherapeutic, immunosuppressive and glucocorticoid agents are used...
June 5, 2018: Journal for Immunotherapy of Cancer
Yangxi Li, Rui Sun
A group of impressive immunotherapies for cancer treatment, including immune checkpoint-blocking antibodies, gene therapy and immune cell adoptive cellular immunotherapy, have been established, providing new weapons to fight cancer. Natural killer (NK) cells are a component of the first line of defense against tumors and virus infections. Studies have shown dysfunctional NK cells in patients with cancer. Thus, restoring NK cell antitumor functionality could be a promising therapeutic strategy. NK cells that are activated and expanded ex vivo can supplement malfunctional NK cells in tumor patients...
April 2018: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
Hassen Kared, Serena Martelli, Shu Wen Tan, Yannick Simoni, Meng Li Chong, Siew Hwei Yap, Evan W Newell, Sylvia L F Pender, Adeeba Kamarulzaman, Reena Rajasuriar, Anis Larbi
Repetitive stimulation by persistent pathogens such as human cytomegalovirus (HCMV) or human immunodeficiency virus (HIV) induces the differentiation of natural killer (NK) cells. This maturation pathway is characterized by the acquisition of phenotypic markers, CD2, CD57, and NKG2C, and effector functions-a process regulated by Tim-3 and orchestrated by a complex network of transcriptional factors, involving T-bet, Eomes, Zeb2, promyelocytic leukemia zinc finger protein, and Foxo3. Here, we show that persistent immune activation during chronic viral co-infections (HCMV, hepatitis C virus, and HIV) interferes with the functional phenotype of NK cells by modulating the Tim-3 pathway; a decrease in Tim-3 expression combined with the acquisition of inhibitory receptors skewed NK cells toward an exhausted and cytotoxic phenotype in an inflammatory environment during chronic HIV infection...
2018: Frontiers in Immunology
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