DOCSLIB.ORG

IL-15 Stimulation with TIGIT Blockade Reverses CD155-Mediated NK Cell

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
IL-15 Stimulation with TIGIT Blockade Reverses CD155-Mediated NK Cell Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/1078-0432.CCR-20-0575 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. IL-15 stimulation with TIGIT blockade reverses CD155-mediated NK cell dysfunction in melanoma Joe-Marc Chauvin1, Mignane Ka1, Ornella Pagliano1, Carmine Menna1, Quanquan Ding1, Richelle DeBlasio1, Cindy Sanders1, Jiajie Hou2, Xian-Yang Li3, Soldano Ferrone4, Diwakar Davar1, John M. Kirkwood1, Robert Johnston5, Alan J. Korman5, Mark J. Smyth3, and Hassane M. Zarour1,6. 1Department of Medicine and Division of Hematology/Oncology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA. 2Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. 3Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Queensland, Australia. 4Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. 5Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA 94063, USA. 6Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA. Running title: IL-15 and TIGIT blockade reverse NK dysfunction in melanoma Keywords: Melanoma, Immunotherapy, TIGIT, IL-15, NK cells This work was supported by NIH/NCI grants R01CA228181 and R01CA222203 (to HMZ), a research grant by Bristol-Myers Squibb BMS (to HMZ), a cancer vaccine collaborative clinical strategy team grant (to HMZ), and NCI grant P50CA121973 (to 1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/1078-0432.CCR-20-0575 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. JMK). MJS was supported by a National Health and Medical Research Council of Australia (NH&MRC) Senior Principal Research Fellowship (1078671), a NH&MRC Program grant (1132519), a NH&MRC Project grant (1124784), a CLIP award from the Cancer Research Institute (New-York, NY), and a Project Grant from the Cancer Council of Queensland (1140251). This work benefited from ImageStreamX MARKII grant NIH 1S10OD019942-01. Address correspondence and reprint requests to Dr. Hassane M. Zarour, Hillman Cancer Center, Research Pavilion, Suite 1.32a, 5117 Centre Avenue, Pittsburgh, PA 15213-2582, Phone: 412 623 3272 Fax: 412 623 7704 Email: [email protected] MJS has a scientific research agreement with Bristol Myers Squibb and Tizona Therapeutics and is on the scientific advisory board of Tizona Therapeutics and Compass Therapeutics. 2 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/1078-0432.CCR-20-0575 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Translational relevance Here, we show that membrane-bound poliovirus receptor (PVR)/CD155 triggers CD226 internalization and degradation, resulting in decreased NK cell-mediated tumor reactivity. We also show that IL-15 increases TIGIT and CD226 gene expression by tumor- infiltrating NK cells, and together with TIGIT blockade, increases NK cell-mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in vivo. Collectively, our findings support the novel combinatorial therapy with IL-15 together with TIGIT blockade to promote NK cell-mediated destruction of MHC class I-deficient melanoma, which are refractory to CD8+ T cell-mediated immunity and PD-1 blockade. 3 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/1078-0432.CCR-20-0575 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose: Natural Killer (NK) cells play a critical role in tumor immunosurveillance. Multiple activating and inhibitory receptors regulate NK cell-mediated tumor control. The inhibitory receptor TIGIT and its counter-receptor CD226 exert opposite effects on NK cell-mediated tumor reactivity. Experimental design: We evaluated the frequency, phenotype and functions of NK cells freshly isolated from healthy donors and melanoma patients with multiparameter flow cytometry. We assessed TIGIT and CD226 cell surface expression and internalization upon binding to CD155. We evaluated the role of Interleukin (IL)-15 and TIGIT blockade in increasing NK cell-mediated cytotoxicity in vitro and in two mouse models. Results: NK cells are present at low frequencies in metastatic melanoma, are dysfunctional and downregulate both TIGIT and CD226 expression. As compared with TIGIT- NK cells, TIGIT+ NK cells exhibit higher cytotoxic capacity and maturation but paradoxically lower cytotoxicity against CD155+ MHC class I-deficient melanoma cells. Membrane-bound CD155 triggers CD226 internalization and degradation, resulting in decreased NK cell-mediated tumor reactivity. IL-15 increases TIGIT and CD226 gene expression by tumor-infiltrating NK cells (TiNKs) and, together with TIGIT blockade, increases NK cell-mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in two mouse melanoma models. Specific deletion of TIGIT on transferred NK cells enhances the anti-metastatic activity of IL-15, while CD226 blockade decreases the effects of IL-15 and TIGIT blockade. Conclusion: Our findings support the development of novel combinatorial immunotherapy with IL-15 and TIGIT blockade to promote NK cell-mediated destruction 4 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/1078-0432.CCR-20-0575 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. of MHC class I-deficient melanoma, which are refractory to CD8+ T cell-mediated immunity. 5 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/1078-0432.CCR-20-0575 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction There is ample evidence that NK cells exhibit tumor-killing capacity and play a critical role in mediating tumor immunosurveillance of primary tumors and controlling metastases (1). NK cells express multiple activating receptors (ARs) and inhibitory receptors (IRs) that regulate their function. Hence, therapeutic strategies to engage ARs and/or counteract NK cell inhibition have the potential to promote NK cell-mediated tumor reactivity (2). Solid tumors are usually poorly infiltrated by NK cells (3), thus the phenotypic and functional studies of TiNKs remain very challenging in humans. TiNKs in ovarian, breast, lung and prostate tumors downregulate multiple ARs, including DNAM-1/CD226, CD16, NKG2D, NKp30, NKp46, and 2B4, and are dysfunctional (4- 9). NK cells upregulate multiple IRs that are also expressed by activated T cells, including CD94/NKG2A (10) and the T cell immunoglobulin and ITIM domain (TIGIT) (11). TIGIT binds with high and low affinity to CD155 (PVR) and CD112 (Nectin-2), respectively which are expressed on monocytes, dendritic cells, and tumor cells, including melanoma, and can also bind to the adhesion protein CD113 (Nectin-3) (12). TIGIT competes with its costimulatory counter-receptor CD226 (DNAM-1), which binds to CD155 with lower affinity (11,12). CD226 competes with CD112R for binding to CD112 (Nectin-2) (13,14). In mouse-bearing tumors and in humans, dual PD-1/TIGIT blockade potently augmented tumor-antigen CD8+ T cell functions and promoted tumor rejection (15,16). TIGIT acts in regulatory T cells (Tregs) to promote tumor growth (17), and CD226 opposes TIGIT to disrupt Treg stability in melanoma (18). Several lines of evidence support the critical role of the TIGIT/CD226 axis in regulating NK cell- mediated antitumor activity. First, TIGIT is highly expressed by circulating human NK 6 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/1078-0432.CCR-20-0575 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. cells (cNKs) and impedes NK cell-mediated killing of tumor cells (11). Upon CD155 binding to TIGIT, the ITT-like motif is phosphorylated and binds to Grb2 to recruit the SH domain-containing inositol-5-phosphatase (SHIP1), impeding PI3 and MAP kinase pathways, and NFKB signaling (19,20). Second, CD226 associates with LFA-1 and is recruited to the immunological synapse to promote NK cell-mediated tumor cytotoxicity (21,22). In vivo, CD226 is involved in NK cell-mediated tumor surveillance and control of melanoma metastases and NK cell-mediated lysis of melanoma (23-26). Third, one recent study in mouse tumor models has suggested that TIGIT acted primarily in NK cells to regulate CD8+ T cell-mediated tumor reactivity (27). Among the various cytokines that expand and activate NK cells, IL-15 potently enhances NK cell-mediated tumor killing and is being actively investigated in many clinical trials (1). NK
Load more

Recommended publications
  • CD226 T Cells Expressing the Receptors TIGIT and Divergent Phenotypes of Human Regulatory
    The Journal of Immunology Divergent Phenotypes of Human Regulatory T Cells Expressing the Receptors TIGIT and CD226 Christopher A. Fuhrman,*,1 Wen-I Yeh,*,1 Howard R. Seay,* Priya Saikumar Lakshmi,* Gaurav Chopra,† Lin Zhang,* Daniel J. Perry,* Stephanie A. McClymont,† Mahesh Yadav,† Maria-Cecilia Lopez,‡ Henry V. Baker,‡ Ying Zhang,x Yizheng Li,{ Maryann Whitley,{ David von Schack,x Mark A. Atkinson,* Jeffrey A. Bluestone,‡ and Todd M. Brusko* Regulatory T cells (Tregs) play a central role in counteracting inflammation and autoimmunity. A more complete understanding of cellular heterogeneity and the potential for lineage plasticity in human Treg subsets may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4+FOXP3+Helios+ thymic-derived Tregs and CD4+FOXP3+Helios2 T cells, followed by comparison with CD4+FOXP32Helios2 T conventional cells. These analyses revealed that the coinhibitory receptor T cell Ig and ITIM domain (TIGIT) was highly expressed on thymic-derived Tregs. TIGIT and the costimulatory factor CD226 bind the common ligand CD155. Thus, we analyzed the cellular distribution and suppressive activity of isolated subsets of CD4+CD25+CD127lo/2 T cells expressing CD226 and/or TIGIT. We observed TIGIT is highly expressed and upregulated on Tregs after activation and in vitro expansion, and is associated with lineage stability and suppressive capacity. Conversely, the CD226+TIGIT2 population was associated with reduced Treg purity and suppressive capacity after expansion, along with a marked increase in IL-10 and effector cytokine production. These studies provide additional markers to delineate functionally distinct Treg subsets that may help direct cellular therapies and provide important phenotypic markers for assessing the role of Tregs in health and disease.
    [Show full text]
  • TIGIT Poster SITC 2018 V.2
    Antitumor efficacy of anti-TIGIT antagonist antibody EOS884448 is mediated by a dual mechanism ofLGO action involving restoration of T cell effector functions and preferential depletion of Tregs. Catherine Hoofd, Julia Cuende, Virginie Rabolli, Julie Preillon, Noémie Wald, Lucile Garnero, Florence Lambolez, Shruthi Prassad, Marjorie Mercier, Florence Nyawame, Margreet Brouwer, Erica Houthuys, Véronique Bodo, Xavier Leroy, Michel Detheux and Gregory Driessens. HIGH TIGIT EXPRESSION ON IMMUNE CELLS, FURTHER SUMMARY TIGIT-DRIVEN IMMUNOSUPPRESSION INCREASED IN CANCER PATIENTS • T cell Immunoreceptor with Ig and ITIM domains (TIGIT) is a negative 1 A. Healthy donors B. Cancer patients costimulatory receptor that inhibits Teff and NK cell function and marks a highly 100 suppressive Treg subset. 2 80 CD4+ T cells CD8+ T cells 60 • TIGIT ligands belong to the PVR/nectin family, among which PVR (CD155) shows Naïve Tr e g 40 the highest affinity and is commonly expressed on antigen presenting cells (APC) Memory % TIGIT+ cells%TIGIT+ % of TIGIT expression Effector and tumor cells. 20 0 • CD226, a co-stimulatory receptor also expressed on NK and T cells, competes γδ TIGIT TCR with TIGIT for PVR binding but with a lower affinity. CD4 Treg CD4 naive T cells CD8 naive T cells CD4 effectorCD4 T cells memory T cells CD8 effectorCD8 T cells memory T cells 100 • TIGIT expression is increased on T and NK(T) cells from cancer patients and is Iguchi-Manaka et al. PLoS One 2016 Johnston RJ et al. Cancer Cell, 2014 80 Killing + correlated to poor outcome and response to aPD1 therapy in some indications. CD4+ T cells CD8 T cells 60 TIGIT phenotyping TIGIT Naïve Tr e g • iTeos developed an anti-human/cyno TIGIT blocking mAb (EOS884448) and a 40 1 drug = multiple anti-tumor mechanisms of action Memory % TIGIT+ cellsTIGIT+ % surrogate anti-mouse TIGIT mAb with comparable properties.
    [Show full text]
  • Cell Function the TIGIT/CD226 Axis Regulates Human T
    The TIGIT/CD226 Axis Regulates Human T Cell Function Ester Lozano, Margarita Dominguez-Villar, Vijay Kuchroo and David A. Hafler This information is current as of September 26, 2021. J Immunol 2012; 188:3869-3875; Prepublished online 16 March 2012; doi: 10.4049/jimmunol.1103627 http://www.jimmunol.org/content/188/8/3869 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2012/03/16/jimmunol.110362 Material 7.DC1 References This article cites 24 articles, 8 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/188/8/3869.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The TIGIT/CD226 Axis Regulates Human T Cell Function Ester Lozano,*,†,‡ Margarita Dominguez-Villar,*,†,‡ Vijay Kuchroo,‡,1 and David A. Hafler*,†,‡,1 T cell Ig and ITIM domain (TIGIT) is a newly identified receptor expressed on T cells that binds to CD155 on the dendritic cell surface, driving them to a more tolerogenic phenotype.
    [Show full text]
  • Antibody Engineers Seek Optimal Drug Targeting TIGIT Checkpoint
    There are amendments to 10.1038/s41587-020-0666-1 news IN this section AI’s role in Biotech news First DBS with COVID-19 from around neurofeedback epidemiology the world approved p1010 p1013 p1014 Antibody engineers seek optimal drug targeting TIGIT checkpoint Four antibodies are already in trials to test efcacy against the emerging checkpoint molecule TIGIT, but debate swirls around the importance of Fc binding for drug action. he race to develop a first-in-class checkpoint-blocking drug is heating Tup, with new clinical data and investor money all buttressing the idea of targeting the co-inhibitory molecule TIGIT (formally known as T cell immunoreceptor with immunoglobulin and ITIM domains) alongside obstruction of the programmed cell death-1 (PD-1) pathway to treat cancer. The combination strategy appears safe and effective against a range of solid tumor types, according to two recent medical meeting reports describing patients treated with Genentech’s fully human IgG1 monoclonal antibody (mAb) tiragolumab, the most advanced anti-TIGIT therapy, now in late-stage clinical development. Others are keeping pace, though, with new funding to test their TIGIT-targeting antibody candidates. In July, for example, iTeos Therapeutics went public, netting $201 million — on top of $125 million in private capital raised earlier in the year — which should allow the company to advance its With or without Fc? Drug makers pursuing anti-TIGIT checkpoint inhibitors are undecided whether human anti-TIGIT IgG1 mAb EOS-448 into the Fc portion of an mAb (lower group in picture) is worth keeping intact. Credit: Kenneth Eward / phase 2 trials.
    [Show full text]
  • TIGIT-Fc Promotes Antitumour Immunity
    bioRxiv preprint doi: https://doi.org/10.1101/2020.10.19.346437; this version posted October 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 TIGIT-Fc Promotes Antitumour Immunity 2 Wenyan Fu1,2, Changhai Lei1, Jian Zhao3 and Shi Hu1, * 3 4 1 Department of Biophysics, College of Basic Medical Sciences, Second Military Medical 5 University, Shanghai 200433, China. 6 2 Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong 7 University School of Medicine, Shanghai 200011, China. 8 3 KOCHKOR Biotech, Inc., Shanghai 202152, China 9 10 *Corresponding Author: Shi Hu, Second Military Medical University, 800 Xiangyin Road, 11 Shanghai, China, 200433. Phone: +86-02181870925. E-mail: [email protected]. 12 13 14 Keywords: Cancer Immunotherapy, TIGIT, Fc fusion, NK cell, T cell 15 16 17 18 19 ~ 1 ~ bioRxiv preprint doi: https://doi.org/10.1101/2020.10.19.346437; this version posted October 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 20 Abstract 21 T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a checkpoint receptor that 22 mediates both T cell and natural killer (NK) cell exhaustion in tumours. An Fc-TIGIT 23 fusion protein was shown to induce an immune-tolerance effect in a previous report, but 24 the relevance of the TIGIT-Fc protein to tumour immunity is unknown. Here, we 25 unexpectedly found that TIGIT-Fc promotes rather than suppresses tumour immunity.
    [Show full text]
  • IL-12 Family Cytokines in Cancer and Immunotherapy
    cancers Review IL-12 Family Cytokines in Cancer and Immunotherapy Bhalchandra Mirlekar 1 and Yuliya Pylayeva-Gupta 1,2,* 1 Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; [email protected] 2 Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA * Correspondence: [email protected] Simple Summary: The IL-12 family cytokines play an important role in regulating the tumor immune contexture. Recent efforts geared towards the development of better immune therapeutic approaches have identified the need to overcome immune suppression and improve the quantity and quality of anti-tumor effector immune cells within the tumor milieu. In this review, we summarize the recent findings on IL-12 family cytokines in regulating anti-tumor immunity as well as the effectiveness and benefits of enhancing anti-tumor immunity in pre-clinical and clinical settings by targeting IL-12 family cytokines. Abstract: The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance.
    [Show full text]
  • Immune Checkpoint Molecules in Natural Killer Cells As Potential Targets for Cancer Immunotherapy
    Signal Transduction and Targeted Therapy www.nature.com/sigtrans REVIEW ARTICLE OPEN Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy Yuqing Cao1, Xiaoyu Wang2, Tianqiang Jin1, Yu Tian1, Chaoliu Dai1, Crystal Widarma3, Rui Song3 and Feng Xu1 Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.
    [Show full text]
  • TIGIT/CD155 Blockade Bioassay, Propagation Model Instructions for Use of Product J2092
    TECHNICAL MANUAL TIGIT/CD155 Blockade Bioassay, Propagation Model Instructions for use of Product J2092 1/18 TM533 TIGIT/CD155 Blockade Bioassay, Propagation Model All technical literature is available at: www.promega.com/protocols/ Visit the web site to verify that you are using the most current version of this Technical Manual. E-mail Promega Technical Services if you have questions on use of this system: [email protected] 1. Description .........................................................................................................................................2 2. Product Components and Storage Conditions ........................................................................................7 3. Before You Begin .................................................................................................................................7 3.A. Materials to Be Supplied by the User ............................................................................................8 3.B. Preparing TIGIT Effector Cells.....................................................................................................8 3.C. Preparing CD155 aAPC/CHO-K1 Cells ....................................................................................... 10 4. Assay Protocol .................................................................................................................................. 11 4.A. Preparing Assay Buffer, Bio-Glo™ Reagent and Antibody Samples ................................................ 11 4.B. Plate Layout
    [Show full text]
  • TIGIT Blockade: a Multipronged Approach to Target the HIV Reservoir
    MINI REVIEW published: 05 May 2020 doi: 10.3389/fcimb.2020.00175 TIGIT Blockade: A Multipronged Approach to Target the HIV Reservoir Kayla A. Holder and Michael D. Grant* Immunology and Infectious Diseases Program, Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada During chronic human immunodeficiency virus type 1 (HIV-1) infection, upregulation of inhibitory molecules contributes to effector cell dysfunction and exhaustion. This, in combination with the ability of HIV-1 to reside dormant in cellular reservoirs and escape immune recognition, makes the pathway to HIV-1 cure particularly challenging. An idealized strategy to achieve HIV-1 cure proposes combined viral and immune activation by “shock”ing HIV-1 out of latency and into an immunologically visible state to be recognized and “kill”ed by immune effector cells. Here we outline the potential for blockade of the inhibitory immune checkpoint T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) to overcome natural killer (NK) cell and T cell inhibition associated with HIV-1 infection and invigorate antiviral effector cell responses against HIV-1 reactivated from the latent cellular reservoir. Edited by: Keywords: HIV-1, TIGIT, PVR, checkpoint inhibitor, T cell, NK cell Andrés Finzi, Université de Montréal, Canada Reviewed by: INTRODUCTION Nicolas Chomont, Université de Montréal, Canada Combination antiretroviral therapy (cART) reduces human immunodeficiency virus type 1 Matthew Parsons, (HIV-1) replication to levels where the amount of viral ribonucleic acid (RNA) in the bloodstream Emory University, United States Catherine A. Blish, falls below current limits of detection. In most cases, maintenance of undetectable viral loads Stanford University, United States requires strict adherence to therapy (Chun et al., 1995, 1997; Finzi et al., 1999).
    [Show full text]
  • Human TIGIT on Porcine Aortic Endothelial Cells Suppresses
    Immunobiology 224 (2019) 605–613 Contents lists available at ScienceDirect Immunobiology journal homepage: www.elsevier.com/locate/imbio Human TIGIT on porcine aortic endothelial cells suppresses xenogeneic macrophage-mediated cytotoxicity T ⁎ Yuki Noguchia, Akira Maedaa, , Pei-Chi Loa, Chihiro Takakuraa, Tomoko Hanedaa, Tasuku Kodamaa, Tomohisa Yoneyamaa, Chiyoshi Toyamaa, Yuko Tazukea, Hiroomi Okuyamaa, Shuji Miyagawaa,b a Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Osaka, Japan b Meiji University International Institute for Bio-Resource Research, Kanagawa, Japan ARTICLE INFO ABSTRACT Keywords: Purpose: The delayed rejection caused by strong cell-mediated innate and adaptive xenogeneic immune re- Xenotransplantation sponses continues to be a major obstacle. Pig-to-Human Therefore, suppressing macrophage function could be effective in avoiding this type of rejection. In this study, Macrophage the suppression of T-cell immunoglobulin and ITIM domain (TIGIT) function against macrophage-mediated TIGIT xenogeneic rejection was investigated. Material and methods: Naïve porcine aortic endothelial cell (PAEC) and PAEC transfectant with TIGIT (PAEC/ TIGIT) were co-cultured with M1 macrophages, and the degree of cytotoxicity was determined by a counting beads assay. The anti/pro-inflammatory gene expression was determined by RT-PCR and the phosphorylated SHP-1 in the macrophages after co-culturing with PAEC or PAEC/TIGIT was evaluated by western blotting. Results: CD155 was expressed at essentially equal levels on both M1 and M2 macrophages, whereas TIGIT was highly expressed on M2 macrophages but not in M1 macrophages. TIGIT on PAEC significantly reduced the cytotoxicity of M1 macrophages but no significant suppression of phagocytosis was detected. TIGIT also caused a decrease in the expression of pro-inflammatory cytokines, namely TNFα, IL-1β and IL-12 in M1 macrophages.
    [Show full text]
  • Inhibitory Functions Cutting Edge: TIGIT Has T Cell-Intrinsic
    Cutting Edge: TIGIT Has T Cell-Intrinsic Inhibitory Functions Nicole Joller, Jason P. Hafler, Boel Brynedal, Nasim Kassam, Silvia Spoerl, Steven D. Levin, Arlene H. Sharpe This information is current as and Vijay K. Kuchroo of October 1, 2021. J Immunol 2011; 186:1338-1342; Prepublished online 3 January 2011; doi: 10.4049/jimmunol.1003081 http://www.jimmunol.org/content/186/3/1338 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2011/01/03/jimmunol.100308 Material 1.DC1 References This article cites 13 articles, 4 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/186/3/1338.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Cutting Edge: TIGIT Has T Cell-Intrinsic Inhibitory Functions † ‡,x Nicole Joller,* Jason{ P. Hafler, Boel Brynedal,‖ Nasim Kassam,* Silvia Spoerl,* Steven D.
    [Show full text]
  • TIGIT-Fc Promote Immune Tolerance at the Feto-Maternal Interface
    bioRxiv preprint doi: https://doi.org/10.1101/819243; this version posted October 28, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. TIGIT-Fc Promote Immune Tolerance at the Feto-maternal Interface Wenyan Fu 1, Zetong Ma2, 3, Changhai Lei2, 3, Min Ding4, Shi Hu2, 3,*. 1 Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200011, China 2 Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China. 3 Team SMMU-China of International Genetically Engineered Machine (iGEM) competitions, Department of Biophysics, Second Military Medical University, Shanghai 200433, China. 4 Pharchoice Therapeutics Inc., Shanghai 201406, China †These authors contribute equally. *Corresponding Author: Shi Hu, Second Military Medical University, 800 Xiangyin Road, Shanghai, China, 200433. Phone: +86-02181870925; E-mail: [email protected] Running title: TIGIT-Fc treatment promote fetomaternal tolerance Keywords: TIGIT, targeted therapy, fetomaternal tolerance, RAS Conflicts of interest：M.D. is employed by Pharchoice Therapeutics Inc. (Shanghai), and is shareholder in Pharchoice Therapeutics Inc. (Shanghai). No potential conflicts of interest were disclosed by the other authors. ~ 1 ~ bioRxiv preprint doi: https://doi.org/10.1101/819243; this version posted October 28, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The perfect synchronization of maternal immune-endocrine mechanisms and those of the foetus is necessary for a successful pregnancy.
    [Show full text]