DOCSLIB.ORG

8 Death Receptor Mutations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
8 Death Receptor Mutations Chapter 8 / Death Receptor Mutations 149 8 Death Receptor Mutations Sug Hyung Lee, MD, PhD, Nam Jin Yoo, MD, PhD, and Jung Young Lee, MD, PhD, SUMMARY It is generally believed that human cancers may arise as the result of an accumulation of mutations in genes and subsequent clonal selection of variant progeny with increas- ingly aggressive behaviors. Also, among the remarkable advances in our understanding in cancer biology is the realization that apoptosis has a profound effect on the malignant phenotypes. Along with these, compelling evidence indicates that somatic mutations in the genes encoding apoptosis-related proteins contribute to either development or pro- gression of human cancers. In this chapter, we present an overview of the death receptor pathway and its dysregulation in cancers. We then review the current knowledge of death receptor mutations that have been detected in humans. INTRODUCTION Programmed cell death through apoptosis plays a fundamental role in a variety of physiological processes, and its deregulation contributes to many diseases, including autoimmunity, cancer, acquisition of drug resistance in tumors, stroke, progression of some degenerative diseases, and acquired immunodeficiency syndrome (AIDS) (1–4). Apoptosis is an active cell-suicide process executed by a cascade of molecular events involving a number of membrane receptors and cytoplasmic proteins (1–4). Although many pathways for activating caspases may exist, only two, the intrinsic pathway and the extrinsic pathway, have been demonstrated in detail (3). The extrinsic pathway can be induced by members of the tumor necrosis factor (TNF) receptor family, such as TNF receptor 1 (TNFR1) and Fas (5–7). These proteins recruit adaptor proteins, including FADD, to their cytosolic death domains, which then bind caspases-8 and -10 (8–12). The intrinsic pathway can be induced by release of cytochrome c from mitochondria (13–15). In the cytosol, cytochrome c binds and activates apaf-1, allowing it to bind and activate caspase-9 (14,15). Active initiator caspases of the extrinsic pathway (caspases-8 and -10) From: Cancer Drug Discovery and Development: Death Receptors in Cancer Therapy Edited by: W. S. El-Deiry © Humana Press Inc., Totowa, NJ 149 150 Lee, Yoo, and Lee and the intrinsic pathway (caspase-9) have been shown to directly cleave and activate the effector protease, caspase-3 (16,17). Also, though commonly viewed as separate path- ways and capable of functioning independently, cross-talk can occur between these path- ways at multiple levels, depending on the repertoire of apoptosis-modulating proteins expressed (18–21). APOPTOSIS AND CANCER Several lines of evidence indicate that tumorigenesis is a multistep process and that these steps reflect genetic alterations that drive the progressive transformation of normal cells into malignant phenotypes (22). The genomes of tumor cells are invariably altered at multiple sites, having suffered disruption through lesions as subtle as point mutations and as obvious as changes in chromosome complement (23). In the multistep tumorigen- esis model, mutations in key cellular genes produce a series of acquired capabilities that allow the developing cancer cell to grow unchecked in the absence of growth-stimulating signals, while overcoming growth-inhibitory signals and host immune responses (22– 25). They also allow the tumor to replicate indefinitely, maintain an oxygen and nutrient supply, and invade adjacent and distant tissues (26–29). Finally, the ability of cells to evade apoptosis is also an essential hallmark of cancer (22,30,31). Since the discovery of bcl-2 as an oncogene that promotes cell survival, it has been widely acknowledged that antiapoptotic genetic lesions are necessary for tumors to arise (32,33). Clonal expansion and tumor growth are the results of the deregulation of intrinsic proliferation (cell division) and cell death (apoptosis). The evidence is mounting, from studies in mouse models and cultured cells, as well as from descriptive analyses of tumor tissues along the multistep carcinogenesis (22,23). Enhanced cell survival is needed at several steps during tumorigenesis: deregulated oncogene expression not only leads to accelerated proliferation, but concomitantly induces apoptosis, which needs to be sup- pressed for the transformed cell to survive and multiply (34). The tumor cells can persist in a hostile environment. For example, sufficient nutrition for every tumor cell becomes restricted; starvation of tumor cells from cytokines usually leads to apoptotic cell death (26,27). Finally, defective apoptosis facilitates metastasis (22). To metastasize, a tumor cell must acquire the ability to survive in the bloodstream and invade a foreign tissue. Normally, this process is prevented by the propensity of epithelial cells to die in suspen- sion, or in the absence of appropriate tissue survival. During metastasis, cancer cells can ignore restraining signals from neighbors and survive detachment from the extracellular matrix (29). Hence, loss of apoptosis can impact tumor development, progression, and metastasis. Loss of apoptosis is also a significant impediment to anticancer therapy. It is now well established that anticancer agents induce apoptosis, and the disruption of apoptotic machineries reduces treatment sensitivity (35). The mutations that favored tumor development dampen the response to chemotherapy, and treatment might select more refractory clones. DEATH RECEPTORS Cell surface death receptors transmit an apoptosis signal on binding of a specific death ligand (2). The best known family of death receptors is represented by tumor necrosis factor receptors (TNFRs), Fas (CD95, Apo-1), and TNF-related apoptosis-inducing Chapter 8 / Death Receptor Mutations 151 ligand receptors (TRAIL-Rs) (36-41). The receptors’ ligands comprise another related family that includes TNF, CD95 ligand (FasL/CD95L), and TRAIL (2). Each of the ligands is synthesized as a membrane-associated protein and shares a characteristic 150- amino-acid region towards the C-terminus by which each ligand interacts with its cognate receptor (2). For the most part, these ligands exist as trimeric or multimeric membrane- bound proteins that may function to induce receptor aggregation. The Fas-FasL system has been recognized as a major pathway for the induction of apoptosis in cells and tissues (1,2). Fas is a member of the death receptor subfamily of the TNFR superfamily (37–39). Ligation of Fas by either agonistic antibody or by its natural ligand transmits a death signal to the target cells, potentially triggering apoptosis. Fas has three cystein-rich extracellular domains and an intracellular death domain (DD) essential for signaling (37–39). The death domain, a name deriving from its ability to recruit downstream effectors that can induce apoptosis, is present in the cytoplasmic tail of all death receptors (1). The death domain is a protein interaction module consisting of a compact bundle of six _-helices (42). Death domains bind each other, probably forming oligomers of unknown stoichiom- etry. Stimulation of Fas results in aggregation of its intracellular death domain, leading to the recruitment of two key signaling proteins that, together with the receptor, form the death-inducing signaling complex (DISC) (43). FADD/MORT-1 (8) couples through its C-terminal death domain to crosslinked Fas receptors and recruits caspase-8 (9) through its N-terminal death effector domain (DED) to the DISC. Caspase-10 (Mch4/FLICE2) is a caspase homologous to caspase-8 and is present as an inactive proenzyme, comprising a prodomain that contains two DEDs to allow caspase-10 to interact with the DED of FADD and a catalytic protease domain that can be further processed to give a large and a small subunit (44). The local aggregation of the procaspases-8 and -10 is sufficient to allow autoprocessing or transprocessing to produce active caspases-8 and -10, which can subsequently activate downstream executioners, such as caspases 3 and 7 (44). Five receptors have been identified for TRAIL, including two apoptosis-inducing receptors (death receptor 4/TRAIL-R1 and DR5/TRICK-2/TRAIL-R2/KILLER-DR7), two decoy receptors (DcRs) (TRID/DcR1 and TRUNDD/DcR2), and osteo-progeterin. TRAIL induces apoptosis through DR4 and DR5 requiring FADD, caspase-8 and caspase- 10, just like CD95-mediated cell killing (45). DEATH RECEPTOR MUTATIONS Fas, DR5, and DR4 are widely expressed in normal and neoplastic cells (46,47), but the expression of these proteins does not necessarily predict susceptibility to killing (48,49). This can reflect the presence of inhibiting mechanisms of death receptor-medi- ated apoptosis. Fas-mediated apoptosis can be blocked by several mechanisms, including the production of soluble Fas (50), the lack of cell-surface Fas expression (51–53), the overexpression of inhibitory proteins in signal transduction pathways such as Fas-asso- ciated phosphatase-1 (54) and FLICE- inhibitory protein (FLIP) (55), and the mutation of the primary structure of Fas (56–65). TRAIL-induced apoptosis can be blocked by several mechanisms, including the expression of decoy receptors for TRAIL (10), the loss of TRAIL receptor expression (5), the overexpression of inhibitory proteins in signal transduction pathways such as FLIP (7), and the mutation of the primary structure of DR4 and DR5 (11). 152 Lee, Yoo, and Lee Germline Mutation of Death Receptors The consequences of naturally occurring mutants of Fas/FasL have been well demon- strated in both mice and humans. lpr and gld are mutations in mice of Fas and FasL, respectively (56,66). Because the Fas/FasL system is involved in the apoptotic process that occurs during cell muturation, lpr and gld mutations result in the development of lymphadenopathy and autoimmune diseases in the mice (67). To date, two lpr mutations are known: lpr and lprcg. The mouse Fas gene consists of over 70kb, and is split by 9 exons (56). The restriction mapping of the Fas gene from lpr mice has revealed the insertion of an early transposable element (ETn) of 5.4 kb in intron 2. The ETn is a mouse endogenous retrovirus, of which about 1,000 copies can be found in the mouse genome.
Load more

Recommended publications
  • The TNF and TNF Receptor Review Superfamilies: Integrating Mammalian Biology
    Cell, Vol. 104, 487±501, February 23, 2001, Copyright 2001 by Cell Press The TNF and TNF Receptor Review Superfamilies: Integrating Mammalian Biology Richard M. Locksley,*²³k Nigel Killeen,²k The receptors and ligands in this superfamily have and Michael J. Lenardo§k unique structural attributes that couple them directly to *Department of Medicine signaling pathways for cell proliferation, survival, and ² Department of Microbiology and Immunology differentiation. Thus, they have assumed prominent ³ Howard Hughes Medical Institute roles in the generation of tissues and transient microen- University of California, San Francisco vironments. Most TNF/TNFR SFPs are expressed in the San Francisco, California 94143 immune system, where their rapid and potent signaling § Laboratory of Immunology capabilities are crucial in coordinating the proliferation National Institute of Allergy and Infectious Diseases and protective functions of pathogen-reactive cells. National Institutes of Health Here, we review the organization of the TNF/TNFR SF Bethesda, Maryland 20892 and how these proteins have been adapted for pro- cesses as seemingly disparate as host defense and or- ganogenesis. In interpreting this large and highly active Introduction area of research, we have focused on common themes that unite the actions of these genes in different tissues. Three decades ago, lymphotoxin (LT) and tumor necro- We also discuss the evolutionary success of this super- sis factor (TNF) were identified as products of lympho- familyÐsuccess that we infer from its expansion across cytes and macrophages that caused the lysis of certain the mammalian genome and from its many indispens- types of cells, especially tumor cells (Granger et al., able roles in mammalian biology.
    [Show full text]
  • The Role of Immunogenic Cell Death
    University of Southern Denmark Current approaches for combination therapy of cancer The role of immunogenic cell death Asadzadeh, Zahra; Safarzadeh, Elham; Safaei, Sahar; Baradaran, Ali; Mohammadi, Ali; Hajiasgharzadeh, Khalil; Derakhshani, Afshin; Argentiero, Antonella; Silvestris, Nicola; Baradaran, Behzad Published in: Cancers DOI: 10.3390/cancers12041047 Publication date: 2020 Document version: Final published version Document license: CC BY Citation for pulished version (APA): Asadzadeh, Z., Safarzadeh, E., Safaei, S., Baradaran, A., Mohammadi, A., Hajiasgharzadeh, K., Derakhshani, A., Argentiero, A., Silvestris, N., & Baradaran, B. (2020). Current approaches for combination therapy of cancer: The role of immunogenic cell death. Cancers , 12(4), [1047]. https://doi.org/10.3390/cancers12041047 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 04. Oct. 2021 cancers Review Current
    [Show full text]
  • Activating Death Receptor DR5 As a Therapeutic Strategy for Rhabdomyosarcoma
    International Scholarly Research Network ISRN Oncology Volume 2012, Article ID 395952, 10 pages doi:10.5402/2012/395952 Review Article Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma Zhigang Kang,1, 2 Shi-Yong Sun,3 and Liang Cao1 1 Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA 2 Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., NCI Frederick, Frederick, MD 21702, USA 3 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA Correspondence should be addressed to Liang Cao, [email protected] Received 4 January 2012; Accepted 24 January 2012 Academic Editors: E. Boven and S. Mandruzzato Copyright © 2012 Zhigang Kang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. It is believed to arise from skeletal muscle progenitors, preserving the expression of genes critical for embryonic myogenic development such as MYOD1 and myogenin. RMS is classified as embryonal, which is more common in younger children, or alveolar, which is more prevalent in elder children and adults. Despite aggressive management including surgery, radiation, and chemotherapy, the outcome for children with metastatic RMS is dismal, and the prognosis has remained unchanged for decades. Apoptosis is a highly regulated process critical for embryonic development and tissue and organ homeostasis. Like other types of cancers, RMS develops by evading intrinsic apoptosis via mutations in the p53 tumor suppressor gene.
    [Show full text]
  • Multiple Interactions of the Cytosolic Polyproline Region of the CD95
    FEBS 25561 FEBS Letters 509 (2001) 255^262 View metadata, citation and similar papers at core.ac.uk brought to you by CORE Multiple interactions of the cytosolic polyproline region ofprovided the by CD95 Elsevier - Publisher Connector ligand: hints for the reverse signal transduction capacity of a death factor1 Jennifer Wenzela;2, Ralf Sanzenbachera;2, Markus Ghadimia, Marc Lewitzkyb, Qingchun Zhouc, David R. Kapland, Dieter Kabelitza, Stephan M. Fellerb, Ottmar Janssena;* aInstitute for Immunology, Christian-Albrechts-University, MichaelisstraMe 5, 24105 Kiel, Germany bCell Signalling Laboratory, Imperial Cancer Research Fund, University of Oxford, Institute of Molecular Medicine, John Radcli¡e Hospital, Headington, Oxford, UK cInstitute of Organic Synthesis, Center China Normal University, 430079 Wuhan, PR China dDepartment of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA Received 19 September 2001; revised 7 November 2001; accepted 7 November 2001 First published online 20 November 2001 Edited by Giulio Superti-Furga regulate activation of CD4- and CD8-positive T cells in Abstract The CD95/Fas/Apo-1 ligand is expressed on activated lymphocytes, NK cells, platelets, certain immune-privileged cells vivo. Upon stimulation with T cell receptor (TCR) agonists and some tumor cells and induces apoptosis through the death in the presence of CD95, cell cycle progression of CD4-pos- receptor CD95/Fas/Apo-1. In murine T cells, membrane-bound itive cells was found to be inhibited [14^16], while CD8-pos- CD95L (Fas ligand) also acts as a costimulatory receptor to itive cells were activated to proliferate [13^16]. The molecular coordinate activation and function in vivo.
    [Show full text]
  • Pro- and Anti-Apoptotic CD95 Signaling in T Cells Maren Paulsen* and Ottmar Janssen
    Paulsen and Janssen Cell Communication and Signaling 2011, 9:7 http://www.biosignaling.com/content/9/1/7 DEBATE Open Access Pro- and anti-apoptotic CD95 signaling in T cells Maren Paulsen* and Ottmar Janssen Abstract The TNF receptor superfamily member CD95 (Fas, APO-1, TNFRSF6) is known as the prototypic death receptor in and outside the immune system. In fact, many mechanisms involved in apoptotic signaling cascades were solved by addressing consequences and pathways initiated by CD95 ligation in activated T cells or other “CD95-sensitive” cell populations. As an example, the binding of the inducible CD95 ligand (CD95L) to CD95 on activated T lymphocytes results in apoptotic cell death. This activation-induced cell death was implicated in the control of immune cell homeostasis and immune response termination. Over the past years, however, it became evident that CD95 acts as a dual function receptor that also exerts anti-apoptotic effects depending on the cellular context. Early observations of a potential non-apoptotic role of CD95 in the growth control of resting T cells were recently reconsidered and revealed quite unexpected findings regarding the costimulatory capacity of CD95 for primary T cell activation. It turned out that CD95 engagement modulates TCR/CD3-driven signal initiation in a dose- dependent manner. High doses of immobilized CD95 agonists or cellular CD95L almost completely silence T cells by blocking early TCR-induced signaling events. In contrast, under otherwise unchanged conditions, lower amounts of the same agonists dramatically augment TCR/CD3-driven activation and proliferation. In the present overview, we summarize these recent findings with a focus on the costimulatory capacity of CD95 in primary T cells and discuss potential implications for the T cell compartment and the interplay between T cells and CD95L-expressing cells including antigen-presenting cells.
    [Show full text]
  • Potential Tumor-Promoting Effects of Ectopic Cd137 Expression on Hodgkin Lymphoma
    POTENTIAL TUMOR-PROMOTING EFFECTS OF ECTOPIC CD137 EXPRESSION ON HODGKIN LYMPHOMA HO WENG TONG (B. Sci (Biomedical Sci.), UPM, Malaysia) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHYSIOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2013 i Acknowledgement I would like to take this opportunity to address my appreciation to my thesis supervisor, Associate Professor Herbert Schwarz, who had provided me with exceptional guidance and advice throughout my candidature. Besides that, he also gave me a lot of supports and this study would not be possible without his truly contributions. I would also like to thank Dr. Shao Zhe, Dr Jiang Dongsheng and Dr Shaqireen for guiding me through basic laboratory technique when I first joined the group, Dr. Gan Shu Uin, Dr. Angela Moh and Ms Tan Teng Ee for assisting me in the generation of transfected and knock down cell lines, and Ms Lee Shu Ying from the confocal unit, NUHS, for providing the necessary facility for my confocal imaging. In addition, I would also like to show my appreciation to Ms Pang Wan Lu who worked closely with me in this Hodgkin lymphoma project. Last but not least, I would also like to express my pleasure to work with all the members from Herbert Schwarz' laboratory, especially Zulkarnain, Qianqiao, Liang Kai and Andy who gave me a lot of support both technically and morally. ii TABLE OF CONTENTS DECLARATION i ACKNOWLEDGEMENT ii TABLE OF CONTENTS iii ABSTRACT vii LIST OF TABLES ix LIST OF FIGURES x LIST OF ABBREVIATION xii 1. INTRODUCTION 1 1.1 Hodgkin lymphoma 2 1.1.1 Etiology and pathophysiology 3 1.1.2 Immunosuppressive microenvironment 6 1.1.3 Association of HL with members of tumor necrosis 8 factor receptor family 1.2 CD137 and CD137L 1.2.1 Expression and characteristic of CD137 and 12 CD137L 1.2.2 Targeting CD137 for immunotherapy 16 1.2.3 CD137 and CD137L in malignant diseases 18 1.3 Trogocytosis 19 1.4 Research objectives 22 iii 2.
    [Show full text]
  • Human Melanoma-Reactive CD4+ and CD8+ CTL Clones Resist Fas
    Human Melanoma-Reactive CD4+ and CD8+ CTL Clones Resist Fas Ligand-Induced Apoptosis and Use Fas/Fas Ligand-Independent Mechanisms for Tumor Killing This information is current as of September 29, 2021. Licia Rivoltini, Marina Radrizzani, Paola Accornero, Paola Squarcina, Claudia Chiodoni, Arabella Mazzocchi, Chiara Castelli, Paolo Tarsini, Vincenzo Viggiano, Filiberto Belli, Mario P. Colombo and Giorgio Parmiani J Immunol 1998; 161:1220-1230; ; Downloaded from http://www.jimmunol.org/content/161/3/1220 References This article cites 60 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/161/3/1220.full#ref-list-1 http://www.jimmunol.org/ 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 29, 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 © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Human Melanoma-Reactive CD41 and CD81 CTL Clones Resist Fas Ligand-Induced Apoptosis and Use Fas/Fas Ligand-Independent Mechanisms for Tumor Killing1 Licia Rivoltini,2* Marina Radrizzani,* Paola Accornero,* Paola Squarcina,* Claudia Chiodoni,* Arabella Mazzocchi,* Chiara Castelli,* Paolo Tarsini,* Vincenzo Viggiano,† Filiberto Belli,‡ Mario P.
    [Show full text]
  • Increased Expression of CD154 and FAS in SLE Patients’ Lymphocytes Maria Elena Manea, Ruediger B
    Increased expression of CD154 and FAS in SLE patients’ lymphocytes Maria Elena Manea, Ruediger B. Mueller, Doru Dejica, Ahmed Sheriff, Georg Schett, Martin Herrmann, Peter Kern To cite this version: Maria Elena Manea, Ruediger B. Mueller, Doru Dejica, Ahmed Sheriff, Georg Schett, et al.. Increased expression of CD154 and FAS in SLE patients’ lymphocytes. Rheumatology International, Springer Verlag, 2009, 30 (2), pp.181-185. 10.1007/s00296-009-0933-4. hal-00568285 HAL Id: hal-00568285 https://hal.archives-ouvertes.fr/hal-00568285 Submitted on 23 Feb 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Increased expression of CD154 and FAS in SLE patients’ lymphocytes Maria Elena Manea1‡, MD, Ruediger B. Mueller2,3‡, MD, Doru Dejica1, PhD, Ahmed Sheriff2, PhD, Georg Schett2, MD, Martin Herrmann2, PhD, Peter Kern4, MD 1 Department of Immunopathology. “Iuliu Hatieganu" University of Medicine and Pharmacy, Str Croitorilor no 19-21, 3400 Cluj-Napoca, Romania. 2 Department for Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nürnberg, Germany 3 Departement of Rheumatologie, Kantonsspital St. Gallen, Switzerland 4 Franz von Prümmer Klinik, Bahnhofstraße 16, 97769 Bad Brückenau, Germany ‡ both authors equally contributed to the work Address correspondence and reprint requests to: Ruediger B.
    [Show full text]
  • A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-Cell Immunotherapy
    Published OnlineFirst December 17, 2020; DOI: 10.1158/2159-8290.CD-20-0756 RESEARCH BRIEF A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy Ranjan Upadhyay1,2,3, Jonathan A. Boiarsky1,2,3, Gvantsa Pantsulaia1,2,3, Judit Svensson-Arvelund1,2,3, Matthew J. Lin1,2,3, Aleksandra Wroblewska2,3,4, Sherry Bhalla3,4, Nathalie Scholler5, Adrian Bot5, John M. Rossi5, Norah Sadek1,2,3, Samir Parekh1,2,3, Alessandro Lagana4, Alessia Baccarini2,3,4, Miriam Merad2,3,6, Brian D. Brown2,3,4, and Joshua D. Brody1,2,3 ABSTRACT T cell–based therapies have induced cancer remissions, though most tumors ulti- mately progress, reflecting inherent or acquired resistance including antigen Bianca Dunn by Illustration escape. Better understanding of how T cells eliminate tumors will help decipher resistance mecha- nisms. We used a CRISPR/Cas9 screen and identified a necessary role for Fas–FasL in antigen-specific T-cell killing. We also found that Fas–FasL mediated off-target “bystander” killing of antigen-negative tumor cells. This localized bystander cytotoxicity enhanced clearance of antigen-heterogeneous tumors in vivo, a finding that has not been shown previously. Fas-mediated on-target and bystander killing was reproduced in chimeric antigen receptor (CAR-T) and bispecific antibody T-cell models and was augmented by inhibiting regulators of Fas signaling. Tumoral FAS expression alone predicted survival of CAR-T–treated patients in a large clinical trial (NCT02348216). These data suggest strate- gies to prevent immune escape by targeting both the antigen expression of most tumor cells and the geography of antigen-loss variants.
    [Show full text]
  • CD95 Ligand - Death Factor and Costimulatory Molecule?
    Cell Death and Differentiation (2003) 10, 1215–1225 & 2003 Nature Publishing Group All rights reserved 1350-9047/03 $25.00 www.nature.com/cdd Review CD95 ligand - death factor and costimulatory molecule? O Janssen*,1, J Qian1, A Linkermann1 and D Kabelitz1 Tissue and Cellular Expression of CD95L 1 Institute for Immunology, Medical Center Schleswig-Holstein, Campus Kiel, Michaelisstrasse 5, D-24105 Kiel, Germany The CD95 ligand (CD95L, Apo-1L, FasL, CD178) is a 281- * Corresponding author: O Janssen. Tel: þ 49-431-5973377; Fax: þ 49-431- amino-acid-containing type II transmembrane protein of the 5973335; E-mail: [email protected] TNF family of death factors (Figure 1).1 Its death-inducing function is best documented in the context of activation- Received 24.4.03; revised 12.6.03; accepted 20.6.03; published online 1 August 2003 induced cell death (AICD) in T cells.2 CD95L is expressed as a Edited by T Ferguson death factor in cytotoxic T lymphocytes (CTL) to kill virally infected or transformed target cells and in natural killer (NK) cells, where it is upregulated by CD16 engagement and 3 Abstract cytokines including IL-2 and IL-12. Similarly, high levels of intracellular CD95L have been detected in monocytic cells The CD95 ligand is involved as a death factor in the with an inducible release upon activation.4 Under physiologi- regulation of activation-induced cell death, establishment cal conditions, CD95L is implicated in the control of erythroid of immune privilege and tumor cell survival. In addition, differentiation,5 angiogenesis in the eye6 and skin home- 7 CD95L may serve as a costimulatory molecule for T-cell ostasis.
    [Show full text]
  • Interaction Apoptosis Mediated by Fas/Fas Ligand Osteoclast Formation In
    Effect of IL-12 on TNF-α-Mediated Osteoclast Formation in Bone Marrow Cells: Apoptosis Mediated by Fas/Fas Ligand Interaction This information is current as of October 6, 2021. Hideki Kitaura, Noriko Nagata, Yuji Fujimura, Hitoshi Hotokezaka, Noriaki Yoshida and Koji Nakayama J Immunol 2002; 169:4732-4738; ; doi: 10.4049/jimmunol.169.9.4732 http://www.jimmunol.org/content/169/9/4732 Downloaded from References This article cites 54 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/169/9/4732.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 6, 2021 *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 © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Effect of IL-12 on TNF-␣-Mediated Osteoclast Formation in Bone Marrow Cells: Apoptosis Mediated by Fas/Fas Ligand Interaction1 Hideki Kitaura,2* Noriko Nagata,*† Yuji Fujimura,*† Hitoshi Hotokezaka,* Noriaki Yoshida,* and Koji Nakayama† Recently, it has been found that differentiation into osteoclasts is induced by TNF-␣.
    [Show full text]
  • Characterization of Murine CD70, the Ligand of the TNF Receptor Family Member CD 27
    UvA-DARE (Digital Academic Repository) Characterization of murine CD70, the ligand of the TNF receptor family member CD 27 Tesselaar, N.A.; Gravestein, L.A.; van Schijndel, G.; Borst, J.; van Lier, R.A.W. Publication date 1997 Published in The journal of immunology Link to publication Citation for published version (APA): Tesselaar, N. A., Gravestein, L. A., van Schijndel, G., Borst, J., & van Lier, R. A. W. (1997). Characterization of murine CD70, the ligand of the TNF receptor family member CD 27. The journal of immunology, 159, 4959-4965. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:30 Sep 2021 Characterization of Murine CD70, the Ligand of the TNF Receptor Family Member CD27' Kiki Tesselaar,* Loes A.
    [Show full text]