DOCSLIB.ORG

A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-Cell Immunotherapy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read 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. SIGNIFIcancE: This study demonstrates the first report ofin vivo Fas-dependent bystander killing of antigen-negative tumors by T cells, a phenomenon that may be contributing to the high response rates of antigen-directed immunotherapies despite tumoral heterogeneity. Small molecules that target the Fas pathway may potentiate this mechanism to prevent cancer relapse. INTRODUCTION contributing to T-cell priming (4–6) and T cell–intrinsic fac- tors (7, 8) both influence antitumor immunity, but tumor T cell–based immunotherapies—including adoptive transfer cell–intrinsic factors have the most abundant clinical evidence of engineered T cells, bispecific antibodies, and checkpoint for contributing to treatment potency and failures. blockade—have revolutionized cancer treatment. However, The clearest such mechanism is target antigen (Ag) mod- even with the remarkably high response rates of chimeric anti- ulation—expression downregulation, lineage switching, or gen receptor (CAR)-T–treated patients, most either progress emergence of splice variants—which is the most common or relapse within one year (1–3). Microenvironmental factors cause of relapse following CAR-T therapy for B-cell acute 1Department of Medicine, Division of Hematology and Medical Oncology, Corresponding Author: Joshua D. Brody, Icahn School of Medicine at Icahn School of Medicine at Mount Sinai, New York, New York. 2Precision Mount Sinai, 1470 Madison Avenue, 5th Floor, Room 106, New York, NY Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, 10029. Phone: 212-241-6756; E-mail: [email protected] 3 New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Cancer Discov 2021;11:1–15 New York, New York. 4Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. 5Kite Pharma, doi: 10.1158/2159-8290.CD-20-0756 Santa Monica, California. 6Department of Oncological Sciences, Icahn ©2020 American Association for Cancer Research. School of Medicine at Mount Sinai, New York, New York. Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). March 2021 CANCER DISCOVERY | OF1 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst December 17, 2020; DOI: 10.1158/2159-8290.CD-20-0756 RESEARCH BRIEF Upadhyay et al. lymphoblastic leukemia (B-ALL; ref. 9). Similar mechanisms an even better predictor of long-term CAR-T therapy out- of Ag escape have also been noted in CAR-T therapy for non- comes than expression of the target molecule, which may Hodgkin lymphoma (NHL; ref. 9), multiple myeloma (10), suggest that homogeneity of Ag expression is not needed to and glioblastoma multiforme (11). Although downregulation achieve full efficacy of Ag-directed therapies. Finally, we pre- of target Ag is a well-characterized occurrence, comparable sent evidence and rationale for combination strategies that rates of Ag+ relapses (12) that are unresponsive to CAR-T rein- augment both on-target and bystander cytotoxic pathways fusion (13–15) also indicate the presence of other immune in order to prevent both Ag+ and Ag− relapses after adoptive evasion mechanisms in tumor cells such as suppression of T-cell therapies. apoptotic pathways. The majority of preclinical and clinical data suggest that RESULTS the tumoricidal effects of murine and human T cells are perforin- and granzyme-mediated (16–18). Consequently, Fas Is a Critical T-Cell Effector Molecule expression of these and other effector molecules (e.g., IFNγ Using a reductionist 3-cell system comprising GFP-spe- and TNFα) is the primary focus of clinical biomarker studies cific (JEDI) CD8 T cells (29, 30), Ag+ A20-GFP cells, and across T cell–based therapies (19–22). However, equal efficacy Ag− A20-mCherry cells (Fig. 1A), we exerted strong iterative of adoptive cell therapy (23) and checkpoint blockade (24) in Ag-specific T-cell selection pressure on the GFP+ popula- perforin-deficient murine models, as well as recent evidence tion (Supplementary Fig. S1A) and sequenced surviving of death receptor signaling gene signatures correlating with cells to measure changes in the frequency of targeted genes CAR-T efficacy (25), supports the notion that other mecha- (Supplementary Fig. S1B). The 291 genes targeted in the nisms may have an underappreciated role in T-cell cytotoxic- screen (Supplementary Table S1) were manually curated ity and warrant further investigation. for high expression in our cancer model and enriched for Additionally, even with optimal Ag-specific tumor clear- immune-related functional annotations. Significant devia- ance, emergence of preexisting Ag-null variants is an tions from the expected frequency of targeted genes in expected mechanism of rapid relapse. Thus, the frequency of the GFP+ cells were internally controlled by the measured durable immunotherapy remissions despite tumoral Ag het- frequency in mCherry+ cells (Supplementary Fig. S1C). erogeneity is surprising. A majority of patients with B-ALL As expected, knockout clones of B2m and Tap1 (Supple- harbor >1% CD19− cells at diagnosis (26), though only ∼20% mentary Fig. S1D and S1E), genes crucial to Ag presen- of patients relapse with CD19− disease after CD19-directed tation, became highly enriched following selection (P < therapy (9). Similarly, response rates of CAR-T therapy for 1e−14; Fig. 1B; Supplementary Fig. S1C). Enrichment of NHL are comparable between subgroups with high and low/ Ag+ cells that had lost MHC class I expression was con- negative tumoral CD19 expression (27). Just as puzzling is firmed at the protein level (Supplementary Fig. S1F and that subclonal loss of β2m, effectively abolishing antigen S1G), in addition to the expected relative loss of PD-L1– presentation to CD8 T cells, in MSI-H colorectal tumors deleted cells (Supplementary Fig. S1F and S1H). Surpris- has no apparent effect on PD-1 blockade efficacy (28). These ingly, knockout clones of Fas became equally enriched (P < data are all highly suggestive of bystander cytotoxicity medi- 1e−14; Fig. 1B; Supplementary Fig. S1C and S1I), a finding ating clearance of Ag− cancer subclones. However, there are unique in our model system compared with other recent no published studies identifying tumor cell mechanisms T cell–based screens (31–34). For validation, we created of how this occurs in vivo despite its enormous therapeutic polyclonally derived stable Fas-knockout lines of A20 lym- potential. phoma as well as 4T1 breast cancer (Fig. 1C) that had no To dissect these mechanisms and address these impor- measurable surface Fas protein expression (Supplementary tant knowledge gaps, we performed a CRISPR/Cas9 screen Fig. S2A) and were resistant to Fas-induced cell death using a targeted library of genes highly expressed by the (Supplementary Fig. S2B). Although wild-type (WT) GFP+ A20 murine lymphoma cell line and identified the death cells were depleted by JEDI, both Fas-negative lymphoma receptor Fas as crucial to T-cell cytotoxicity. For the first (Fig. 1D; quantified in Supplementary Fig. S2C) and breast time, we demonstrate that Fas-mediated bystander killing cancer (Fig. 1E; quantified in Supplementary Fig. S2D) enhances in vivo control of heterogeneous tumors. We also demonstrated resistance to killing under the same con- demonstrate that pretreatment tumoral FAS expression is ditions, despite robust T-cell proliferation, granzyme B Figure 1. A pooled CRISPR/Cas9 screen for T cell cytolytic mechanisms identifiesFas as crucial to on-target anticancer immunity. A, Schema depict- ing screening strategy; A20-GFP cells (Ag+; green), A20-mCherry cells (Ag−; red), GFP-specific T cells (blue). NGS, next-generation sequencing. B, Summary of 291-gene screen across four pooled libraries after 0, 1, or 2 iterations
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]
  • 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]
  • CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30 And
    Published OnlineFirst August 7, 2018; DOI: 10.1158/2326-6066.CIR-18-0065 Research Article Cancer Immunology Research CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30þ and CD30– Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions Lee K. Hong1, Yuhui Chen2, Christof C. Smith1, Stephanie A. Montgomery3, Benjamin G. Vincent2, Gianpietro Dotti1,2, and Barbara Savoldo2,4 Abstract Tumor antigen heterogeneity limits success of chimeric (NSG) mouse model of metastatic EC. We observed that CD30. þ antigen receptor (CAR) T-cell therapies. Embryonal carcino- CAR T cells, while targeting CD30 EC tumor cells through mas (EC) and mixed testicular germ cell tumors (TGCT) the CAR (i.e., antigen-dependent targeting), also eliminated – containing EC, which are the most aggressive TGCT subtypes, surrounding CD30 EC cells in an antigen-independent man- are useful for dissecting this issue as ECs express the CD30 ner, via a cell–cell contact-dependent Fas/FasL interaction. In – þ – antigen but also contain CD30 /dim cells. We found that CD30- addition, ectopic Fas (CD95) expression in CD30 Fas EC was redirected CAR T cells (CD30.CAR T cells) exhibit antitumor sufficient to improve CD30.CAR T-cell antitumor activity. activity in vitro against the human EC cell lines Tera-1, Tera-2, Overall, these data suggest that CD30.CAR T cells might be and NCCIT and putative EC stem cells identified by Hoechst useful as an immunotherapy for ECs. Additionally, Fas/FasL dye staining. Cytolytic activity of CD30.CAR T cells was com- interaction between tumor cells and CAR T cells can be plemented by their sustained proliferation and proinflamma- exploited to reduce tumor escape due to heterogeneous antigen tory cytokine production.
    [Show full text]
  • Targeting of the Tumor Necrosis Factor Receptor Superfamily for Cancer Immunotherapy
    Hindawi Publishing Corporation ISRN Oncology Volume 2013, Article ID 371854, 25 pages http://dx.doi.org/10.1155/2013/371854 Review Article Targeting of the Tumor Necrosis Factor Receptor Superfamily for Cancer Immunotherapy Edwin Bremer Department of Surgery, Translational Surgical Oncology, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands Correspondence should be addressed to Edwin Bremer; [email protected] Received 10 April 2013; Accepted 11 May 2013 AcademicEditors:H.Al-Ali,J.Bentel,D.Canuti,L.Mutti,andR.V.Sionov Copyright © 2013 Edwin Bremer. 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. The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamilies constitute an important regulatory axis that is pivotal for immune homeostasis and correct execution of immune responses. TNF ligands and receptors are involved in diverse biological processes ranging from the selective induction of cell death in potentially dangerous and superfluous cells to providing costimulatory signals that help mount an effective immune response. This diverse and important regulatory role in immunity has sparked great interest in the development of TNFL/TNFR-targeted cancer immunotherapeutics. In this review, I will discuss the biology of the most prominent proapoptotic and co-stimulatory TNF ligands and review their current status in cancer immunotherapy. 1. Introduction ligand/receptor interaction induces formation of a Death Inducing Signaling Complex (DISC) to the cytoplasmic DD The tumor necrosis factor (TNF) superfamily is comprised [3]. This DISC comprises the adaptor protein Fas-associated of 27 ligands that all share the hallmark extracellular TNF death domain (FADD) and an inactive proform of the homology domain (THD) [1].
    [Show full text]
  • Activation Cell Homeostasis in Chronic Immune Cutting Edge
    Cutting Edge: CD95 Maintains Effector T Cell Homeostasis in Chronic Immune Activation This information is current as Ramon Arens, Paul A. Baars, Margot Jak, Kiki Tesselaar, of September 24, 2021. Martin van der Valk, Marinus H. J. van Oers and René A. W. van Lier J Immunol 2005; 174:5915-5920; ; doi: 10.4049/jimmunol.174.10.5915 http://www.jimmunol.org/content/174/10/5915 Downloaded from References This article cites 30 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/174/10/5915.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 September 24, 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY CUTTING EDGE Cutting Edge: CD95 Maintains Effector T Cell Homeostasis in Chronic Immune Activation Ramon Arens,1*†‡ Paul A. Baars,* Margot Jak,* Kiki Tesselaar,* Martin van der Valk,§ Marinus H.
    [Show full text]
  • A Small Peptide Antagonist of the Fas Receptor Inhibits Neuroinflammation
    University of Massachusetts Medical School eScholarship@UMMS Open Access Articles Open Access Publications by UMMS Authors 2019-09-30 A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma Anitha Krishnan Harvard Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Amino Acids, Peptides, and Proteins Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Cell Biology Commons, Eye Diseases Commons, Nervous System Commons, Neuroscience and Neurobiology Commons, and the Ophthalmology Commons Repository Citation Krishnan A, Kocab AJ, Zacks DN, Marshak-Rothstein A, Gregory-Ksander M. (2019). A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma. Open Access Articles. https://doi.org/ 10.1186/s12974-019-1576-3. Retrieved from https://escholarship.umassmed.edu/oapubs/3987 Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Articles by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Krishnan et al. Journal of Neuroinflammation (2019) 16:184 https://doi.org/10.1186/s12974-019-1576-3 RESEARCH Open Access A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma Anitha Krishnan1, Andrew J.
    [Show full text]
  • Differential Regulation and Function of Fas Expression on Glial Cells Sung Joong Lee, Tong Zhou, Chulhee Choi, Zheng Wang and Etty N
    Differential Regulation and Function of Fas Expression on Glial Cells Sung Joong Lee, Tong Zhou, Chulhee Choi, Zheng Wang and Etty N. Benveniste This information is current as of September 28, 2021. J Immunol 2000; 164:1277-1285; ; doi: 10.4049/jimmunol.164.3.1277 http://www.jimmunol.org/content/164/3/1277 Downloaded from References This article cites 70 articles, 33 of which you can access for free at: http://www.jimmunol.org/content/164/3/1277.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 28, 2021 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 © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Differential Regulation and Function of Fas Expression on Glial Cells1 Sung Joong Lee,* Tong Zhou,† Chulhee Choi,* Zheng Wang,† and Etty N. Benveniste2* Fas/Apo-1 is a member of the TNF receptor superfamily that signals apoptotic cell death in susceptible target cells. Fas or Fas ligand (FasL)-deficient mice are relatively resistant to the induction of experimental allergic encephalomyelitis, implying the involvement of Fas/FasL in this disease process.
    [Show full text]
  • Human T Cells − CD27 + CD45RA + Effector-Type CD8 Activation
    Cytolytic Mechanisms and Expression of Activation-Regulating Receptors on Effector-Type CD8+CD45RA+CD27− Human T Cells This information is current as of September 29, 2021. Paul A. Baars, Laura M. Ribeiro do Couto, Jeanette H. W. Leusen, Berend Hooibrink, Taco W. Kuijpers, Susanne M. A. Lens and René A. W. van Lier J Immunol 2000; 165:1910-1917; ; doi: 10.4049/jimmunol.165.4.1910 Downloaded from http://www.jimmunol.org/content/165/4/1910 References This article cites 45 articles, 19 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/165/4/1910.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 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 © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Cytolytic Mechanisms and Expression of Activation-Regulating Receptors on Effector-Type CD8؉CD45RA؉CD27؊ Human T Cells Paul A. Baars,1* Laura M.
    [Show 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).
    [Show full text]
  • Death Receptors Couple to Both Cell Proliferation and Apoptosis
    Death receptors couple to both cell proliferation and apoptosis Ralph C. Budd J Clin Invest. 2002;109(4):437-442. https://doi.org/10.1172/JCI15077. Perspective No one will dispute that death receptors do exactly what their name suggests, induce programmed cell death. In addition, however, several reports have recently suggested that these receptors, or their downstream regulators, may also function in certain aspects of cell growth or differentiation. These claims might be met with justifiable skepticism. Certainly there is nothing more opposite in cell fate than growth and death. Yet the signal pathways used by these two processes appear to commingle, and the eventual outcome of the signaling vector may be bent toward one result over the other by seemingly subtle balances among these components. Here, following a brief review of the traditional signal pathways that lead from death receptor activation to apoptosis, I scrutinize the various reports of increased growth or differentiation mediated by these same receptors. I then consider newly identified signal pathways linked to death receptors that might promote growth and, finally, speculate on whether these events represent merely interesting in vitro manipulations or actual physiologically important processes. Conventional death receptor signaling The classical view of death receptor function is typified by Fas (CD95/APO-1), a member of the TNF receptor (TNFR) family (1). Trimerization, or more likely oligomerization of Fas, leads to formation of the death-inducing signal complex (DISC), starting with recruitment of the Fas-adapter protein FADD through their mutual death domains […] Find the latest version: https://jci.me/15077/pdf PERSPECTIVE SERIES Lymphocyte signal transduction Gary Koretzky, Series Editor Death receptors couple to both cell proliferation and apoptosis Ralph C.
    [Show full text]
  • Distinct Effects of CD30 and Fas Signaling in Cutaneous Anaplastic Lymphomas: a Possible Mechanism for Disease Progression
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Distinct Effects of CD30 and Fas Signaling in Cutaneous Anaplastic Lymphomas: A Possible Mechanism for Disease Progression Edi Levi, Zhenxi Wang, Tina Petrogiannis-Haliotis, Walther M. Pfeifer, Werner Kempf, Reed Drews, and Marshall E. Kadin Departments of Pathology and Medicine, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, U.S.A. Lymphomatoid papulosis is part of a spectrum of agonistic antibody, HeFi-1. Proliferative responses, CD30+ cutaneous lymphoproliferative disorders char- mitogen-activated protein kinase, and nuclear factor acterized by spontaneous tumor regression. The kB activities were determined with and without CD30 mechanism(s) of regression is unknown. In a recent activation. Mac-1 and Mac-2 A showed increased pro- study, a selective increase in CD30 ligand expression in liferative responses to incubation with CD30 activating regressing lesions of lymphomatoid papulosis and antibody, HeFi-1. Inhibition of the mitogen-activated cutaneous CD30+ anaplastic large cell lymphoma was protein kinase activity caused growth inhibition of the shown, suggesting that activation of the CD30 signal- Mac-1, Mac-2 A, and JK cell lines. Activation of the ing pathway may be responsible for tumor regression, Fas pathway induced apoptosis in all three cell lines. whereas no difference in Fas/Fas ligand expression Taken together, these ®ndings suggest that resistance was found between regressing and nonregressing to CD30-mediated growth inhibition provides a lesions. Therefore we tested the effects of CD30 and possible mechanism for escape of cutaneous anaplastic Fas activation on three CD30+ cutaneous lymphoma large cell lymphoma from tumor regression.
    [Show full text]
  • Inhibition of Histone Deacetylase Activity Enhances Fas Receptor-Mediated Apoptosis in Leukemic Lymphoblasts
    Cell Death and Differentiation (2001) 8, 1014 ± 1021 ã 2001 Nature Publishing Group All rights reserved 1350-9047/01 $15.00 www.nature.com/cdd Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts ,1,2 1 1,4 3 D Bernhard* , S Skvortsov , I Tinhofer ,HHuÈbl , Introduction R Greil1,4, A Csordas3 and R Ko¯er1,2 In the past few years histone acetylation has been increasingly 1 Tyrolean Cancer Research Institute, Innrain 66, A-6020 Innsbruck, Austria. recognized as being involved in the regulation of gene 2 Institute for General and Experimental Pathology, Division of Molecular transcription (reviewed in1,2). Furthermore, numerous studies Pathophysiology University of Innsbruck, A-6020 Innsbruck, Austria. have reported that inhibitors of histone deacetylases, such as 3 Institute of Medical Chemistry and Biochemistry, University of Innsbruck, the short-chain fatty acid (SCFA) butyrate, cause arrest of cell A-6020 Innsbruck, Austria. 4 division and induction of differentiation markers in animal Laboratory of Molecular Cytology, Division of Hematology and Oncology, 3±5 Department of Internal Medicine, University of Innsbruck, A-6020 Innsbruck, cells but induce programmed cell death in a cell-type Austria. specific manner, and even in the butyrate-sensitive cell types * Corresponding author: D Bernhard, Tyrolean Cancer Research Institute, follow different mechanisms of apoptosis. Butyrate-induced Innrain 66, A-6020 Innsbruck, Austria. Tel.: 0043-512-570485-15; apoptosis in certain colonocytes occurs via a Fas-dependent Fax: 0043-512-570485-44; E-mail: [email protected] pathway6 whereas butyrate-induced apoptosis of leukemic lymphoblasts does not.7 Moreover, butyrate resensitizes Fas- Received 13.3.01; revised 17.5.01; accepted 29.5.01 resistant colonocytes to this form of cell death.8,9 Edited by M Peter Although the underlying mechanisms have not yet been elucidated, these findings suggest that histone acetylation Abstract has an impact on sensitivity to Fas-induced apoptosis.
    [Show full text]