MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies
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It Takes Two to Tango
HIGHLIGHTS IMMUNOTHERAPY It takes two to tango Much of the recent work on the development of active, specific immunotherapy of cancer has focused on the induction of CD8+ cytotoxic T-lymphocyte (CTL) responses, and several studies have shown that it is possible to stimulate tumour-specific CTLs using dendritic cells (DCs) that are loaded with tumour antigens. But CD4+ T-helper type 1 (TH1) cells are also important day of vaccination and loaded with various So, the results from this Phase I trial provide components of effective immune responses. MHC class-I- and -II-restricted peptides. convincing evidence that cryopreserved DCs In this study, Schuler–Thurner and Patients with incurable melanoma were can induce TH1 responses against tumour colleagues provide the first evidence that DCs treated with five biweekly vaccinations of antigens without significant toxicity, and it that are loaded with tumour-specific peptides DCs, followed by assessment one month also encourages further development of can rapidly induce TH1 responses in cancer after the final vaccination. DC-based vaccination technology. patients that are readily detectable ex vivo. The results showed that the vaccination Elaine Bell References and links The DCs that were used for vaccination protocol induced a rapid TH1 response in in this study were derived from blood patients, both to a control immunizing antigen ORIGINAL RESEARCH PAPER Schuler–Thurner, B. et al. Rapid induction of tumor-specific type 1 T helper cells in monocytes that were matured ex vivo using and also to defined MHC class-II-restricted metastatic melanoma patients by vaccination with mature, a defined cocktail (consisting of interleukin tumour antigens. -
Tumor Neoantigens: from Basic Research to Clinical Applications
Jiang et al. Journal of Hematology & Oncology (2019) 12:93 https://doi.org/10.1186/s13045-019-0787-5 REVIEW Open Access Tumor neoantigens: from basic research to clinical applications Tao Jiang1,4†, Tao Shi2†, Henghui Zhang3†,JieHu1, Yuanlin Song1, Jia Wei2*, Shengxiang Ren4* and Caicun Zhou4* Abstract Tumor neoantigen is the truly foreign protein and entirely absent from normal human organs/tissues. It could be specifically recognized by neoantigen-specific T cell receptors (TCRs) in the context of major histocompatibility complexes (MHCs) molecules. Emerging evidence has suggested that neoantigens play a critical role in tumor- specific T cell-mediated antitumor immune response and successful cancer immunotherapies. From a theoretical perspective, neoantigen is an ideal immunotherapy target because they are distinguished from germline and could be recognized as non-self by the host immune system. Neoantigen-based therapeutic personalized vaccines and adoptive T cell transfer have shown promising preliminary results. Furthermore, recent studies suggested the significant role of neoantigen in immune escape, immunoediting, and sensitivity to immune checkpoint inhibitors. In this review, we systematically summarize the recent advances of understanding and identification of tumor- specific neoantigens and its role on current cancer immunotherapies. We also discuss the ongoing development of strategies based on neoantigens and its future clinical applications. Keywords: Neoantigen, Immunotherapy, Immune escape, Immune checkpoint, Resistance Introduction polyomavirus (MCPyV)–related Merkel cell carcinoma Tumor neoantigen, or tumor-specific antigen (TSA), (MCC) and Epstein-Barr virus (EBV)–relatedheadandneck is the repertoire of peptides that displays on the cancers, any epitopes derive from open reading frames tumor cell surface and could be specifically recog- (ORFs) in the viral genome also contribute to the potential nized by neoantigen-specific T cell receptors (TCRs) source of neoantigens [6–8]. -
1 ICAM3-Fc Outperforms Receptor-Specific Antibodies
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 10 April 2019 doi:10.20944/preprints201904.0118.v1 Peer-reviewed version available at Molecules 2019, 24, 1825; doi:10.3390/molecules24091825 ICAM3-Fc outperforms receptor-specific antibodies targeted nanoparticles to dendritic cells for cross-presentation Luis J. Cruz,1* Paul J. Tacken,2 Johan S. van der Schoot,2 Felix Rueda,3 Ruurd Torensma,2 Carl G. Figdor2* 1Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. 2Department of Tumor Immunology, Radboud Insititute for Molecular Life Sciences, Radboud University Medical Center, Postbox 9101, 6500 HB Nijmegen, The Netherlands. 3Department of Biochemistry and Molecular Biology, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain. Running title: ICAM3-Fc- versus antibody-targeted NP vaccines to human DCs Keywords: Delivery system; nanoparticle; targeting. AUTHOR INFORMATION Corresponding Author *Dr. Luis J. Cruz Translational Nanobiomaterials and Imaging, Department of Radiology, Bldg.1, C5-60. Leiden University Medical Center, Albinusdreef 2 2333 ZA Leiden, The Netherlands Tel: +31 71 5263025 Email: [email protected] *Prof. Dr. Carl G. Figdor Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Postbox 9101, 6500 HB Nijmegen, The Netherlands. Fax: +31-24-3540339; Tel.: +31-24-3617600; E-mail: [email protected] 1 © 2019 by the author(s). Distributed -
Regulation of Calreticulin–Major Histocompatibility Complex (MHC) Class I Interactions by ATP
Regulation of calreticulin–major histocompatibility complex (MHC) class I interactions by ATP Sanjeeva Joseph Wijeyesakerea, Jessica K. Gagnonb, Karunesh Arorab, Charles L. Brooks IIIb, and Malini Raghavana,1 aDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; and bDepartment of Chemistry, University of Michigan, Ann Arbor, MI 48109 Edited by Peter Cresswell, Yale University School of Medicine, New Haven, CT, and approved September 1, 2015 (received for review May 26, 2015) The MHC class I peptide loading complex (PLC) facilitates the assembly computational methods validated by experimental approaches, we of MHC class I molecules with peptides, but factors that regulate the identify residues within the globular domain of calreticulin that stability and dynamics of the assembly complex are largely unchar- are important for ATP binding and ATPase activity. Based on acterized. Based on initial findings that ATP, in addition to MHC class further investigations into the functional effects of calreticulin I-specific peptide, is able to induce MHC class I dissociation from the mutants with deficiencies in ATP interactions, we elucidate a key PLC, we investigated the interaction of ATP with the chaperone role for ATP in the regulation of PLC dynamics and the in- calreticulin, an endoplasmic reticulum (ER) luminal, calcium-bind- teraction of calreticulin with other cellular proteins. ing component of the PLC that is known to bind ATP. We combined computational and experimental measurements to identify residues Results within the globular domain of calreticulin, in proximity to the high- ATP Destabilizes the PLC, Promoting MHC Class I Release. Calreticulin- affinity calcium-binding site, that are important for high-affinity ATP deficient mouse embryonic fibroblasts (MEFs) reconstituted binding and for ATPase activity. -
Efficient Elimination of Primary B-ALL Cells in Vitro and in Vivo Using A
Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-000896 on 11 August 2020. Downloaded from Efficient elimination of primary B- ALL cells in vitro and in vivo using a novel 4- 1BB- based CAR targeting a membrane- distal CD22 epitope 1 1 1 Talia Velasco- Hernandez , Samanta Romina Zanetti , Heleia Roca- Ho, Francisco Gutierrez- Aguera,1 Paolo Petazzi,1 Diego Sánchez- Martínez,1 Oscar Molina,1 Matteo Libero Baroni,1 Jose Luis Fuster,2 Paola Ballerini,3 1,4 5 6,7 Clara Bueno, Narcis Fernandez- Fuentes, Pablo Engel , Pablo Menendez1,4,7,8 To cite: Velasco- Hernandez T, ABSTRACT BACKGROUND Zanetti SR, Roca- Ho H, et al. Background There are few therapeutic options available for B-cell acute lymphoblastic leukemia (B-ALL) Efficient elimination of primary patients with B- cell acute lymphoblastic leukemia (B- ALL) is an aggressive cancer, diagnosed at any age B- ALL cells in vitro and in vivo – using a novel 4- 1BB- based relapsing as CD19 either after chemotherapy or CD19- throughout the lifespan of an individual, CAR targeting a membrane- targeted immunotherapies. CD22- chimeric antigen receptor being the most common malignancy in distal CD22 epitope. Journal (CAR) T cells represent an attractive addition to CD19- CAR children.1 Despite current 5-year disease- + – for ImmunoTherapy of Cancer T cell therapy because they will target both CD22 CD19 free survival rates of ~80%, refractory and 2020;8:e000896. doi:10.1136/ B- ALL relapses and CD19– preleukemic cells. However, jitc-2020-000896 relapsed (R/R) patients have a dismal prog- the immune escape mechanisms from CD22- CAR T cells, nosis.2–7 Adult B- ALL is less frequent, but is and the potential contribution of the epitope binding of the commonly associated with an unfavorable ► Additional material is anti-CD22 single-chain variable fragment (scFv) remain published online only. -
Cell Biology from an Immune Perspective in This Lecture We Will
Harvard-MIT Division of Health Sciences and Technology HST.176: Cellular and Molecular Immunology Course Director: Dr. Shiv Pillai Cell Biology from an Immune Perspective In this lecture we will very briefly review some aspects of cell biology which are required as background knowledge in order to understand how the immune system works. These will include: 1. A brief overview of protein trafficking 2. Signal transduction 3. The cell cycle Some of these issues will be treated in greater depth in later lectures. Protein Trafficking/The Secretory Pathway: From an immune perspective the secretory compartment and structures enclosed by vesicles are “seen” in different ways from proteins that reside in the cytosol or the nucleus. We will briefly review the secretory and endocytic pathways and discuss the biogenesis of membrane proteins. Some of the issues that will be discussed are summarized in Figures 1-3. Early endosomes Late endosomes Lysosomes Golgi Vesiculo-Tubular Compartment ER Figure 1. An overview of the secretory pathway Early endosomes Late endosomes Multivesicular and multilamellar bodies Golgi ER Proteasomes Figure 2. Protein degradation occurs mainly in lysosomes and proteasomes Proteins that enter the cell from the environment are primarily degraded in lysosomes. Most cytosolic and nuclear proteins are degraded in organelles called proteasomes. Intriguingly these two sites of degradation are each functionally linked to distinct antigen presentation pathways, different kinds of MHC molecules and the activation of different categories of T cells. Integral membrane proteins maybe inserted into the membrane in a number of ways, the two most common of these ways being considered in Figure 3. -
Innate Immunity: MHC Class I As a Negative Regulator of TLR Signalling
RESEARCH HIGHLIGHTS IN BRIEF T RANSPLANTATION Handling complement for transplant success Haematopoietic cell transplantation (HCT) is used to treat cancer and blood disorders, but a potentially lethal complication is the development of graft-versus-host disease (GVHD). Total-body irradiation (TBI) is required to facilitate HCT and can promote GVHD by activating host dendritic cells (DCs), although the mechanisms involved are not completely understood. This study shows that, in mice, TBI causes host DCs to upregulate the complement components C3, C5a, factor B and factor D, and to downregulate CD55, a negative regulator of the complement cascade. In HCT using CD55-deficient donor T cells, recipient mice developed exacerbated GVHD, suggesting that upregulation of complement components by host DCs promotes the activation of allogeneic donor T cells. Indeed, less severe GVHD was seen in HCT using donor T cells that were deficient in the C3a and C5a receptors. Treatment of recipients with a C5a receptor antagonist during the post-transplantation period reduced GVHD development, and could be a useful strategy for preventing GVHD in humans after transplantation. ORIGINAL RESEARCH PAPER Kwan, W.-H. et al. Antigen-presenting cell-derived complement modulates graft-versus-host disease. J. Clin. Invest. 15 May 2012 (doi:10.1172/JCI61019) T CELLS ‘Leaky’ cytokine secretion by immunological synapses This study used live-cell imaging to investigate whether cytokine secretion by activated T cells is restricted by the immunological synapse to antigen-specific target cells or also affects bystander cells in the local environment. Responses to interferon-γ (IFNγ) were monitored by tracking the intracellular localization of a fluorescent STAT1 protein in ovalbumin- expressing and non-expressing astrocytes cultured with activated ovalbumin-specific CD8+ T cells. -
Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation
University of Massachusetts Medical School eScholarship@UMMS Open Access Publications by UMMS Authors 2021-03-09 Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation Karthik Dhatchinamoorthy University of Massachusetts 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 Factors Commons, Cancer Biology Commons, Hemic and Immune Systems Commons, Immunopathology Commons, Neoplasms Commons, and the Pathology Commons Repository Citation Dhatchinamoorthy K, Colbert JD, Rock KL. (2021). Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. Open Access Publications by UMMS Authors. https://doi.org/10.3389/ fimmu.2021.636568. Retrieved from https://escholarship.umassmed.edu/oapubs/4636 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 Publications by UMMS Authors by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. REVIEW published: 09 March 2021 doi: 10.3389/fimmu.2021.636568 Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation Karthik Dhatchinamoorthy, Jeff D. Colbert and Kenneth L. Rock* Department of Pathology, UMass Medical School, Worcester, MA, United States Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell’s expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. -
The MHC Class I–Like Fc Receptor Promotes Humorally Mediated Autoimmune Disease Shreeram Akilesh, Stefka Petkova, Thomas J
Research article The MHC class I–like Fc receptor promotes humorally mediated autoimmune disease Shreeram Akilesh, Stefka Petkova, Thomas J. Sproule, Daniel J. Shaffer, Gregory J. Christianson, and Derry Roopenian The Jackson Laboratory, Bar Harbor, Maine, USA. The MHC class I family–like Fc receptor, FcRn, is normally responsible for extending the life span of serum IgG Ab’s, but whether this molecule contributes to autoimmune pathogenesis remains speculative. To deter- mine directly whether this function contributes to humoral autoimmune disease, we examined whether a defi- ciency in the FcRn heavy chain influences autoimmune arthritis in the K/BxN mouse model. FcRn deficiency conferred either partial or complete protection in the arthritogenic serum transfer and the more aggressive genetically determined K/BxN autoimmune arthritis models. The protective effects of an FcRn deficiency could be overridden with excessive amounts of pathogenic IgG Ab’s. The therapeutic saturation of FcRn by high-dose intravenous IgG (IVIg) also ameliorated arthritis, directly implicating FcRn blockade as a signifi- cant mechanism of IVIg’s anti-inflammatory action. The results suggest that FcRn is a potential therapeutic target that links the initiation and effector phases of humoral autoimmune disease. Introduction mice been used as a model for addressing this question with mixed At the inductive phase of a humoral autoimmune response, B results (refs. 9–16; D. Roopenian, unpublished observations). This cells, after encounter with APCs and T cells, undergo antigen- is not surprising because β2m controls many immunological and driven proliferation and differentiation into Ab-secreting plasma nonimmunological processes, including the development and cells. During the effector phase, Ab’s bind autoantigen leading function of CD8 T cells, natural T cells, conventional NK cells (17), to downstream events such as activation of complement, recruit- and iron homeostasis (18). -
Pioneering Individualized Cancer Therapies
PLATFORMS Pharmacologically optimized protein coding RNA for targeted in vivo delivery mRNA Technology • Cancer immunotherapies • Prophylactic vaccines • Protein replacement Immunotherapy with genetically engineered T cells, adoptive T cell transfer Cell Therapy • T cell receptor therapies • CAR-T therapies Engineered nanoparticles for cancer immunotherapy • Bispecific antibodies Protein Therapeutics • Microbodies • Virus-like particles Small molecule drug discovery • TLR7-agonists Small Molecules • Immuno-modulating small molecules • Drug discovery services FIRST INDIVIDUALIZED CLINICAL CANCER TRIALS WORLDWIDE WITH • An mRNA-based individualized cancer vaccine targeting neo-antigens • An intravenous formulation of an mRNA vaccine • An mRNA-based individualized vaccine drawn from a warehouse of mRNAs encoding cancer-selective antigens • A genomics-driven GMP-approved manufacturing process for individual patient-specific therapies PIONEERING INDIVIDUALIZED BioNTech SE An der Goldgrube 12 CANCER THERAPIES 55131 Mainz Germany +49 6131 – 9084 – 0 [email protected] www.biontech.de/de COMPANY OVERVIEW INDIVIDUALIZED MRNA IMMUNOLOGY BioNTech is the largest privately held biopharmaceutical company in Europe. CONCEPTS – A BIONTECH PLATFORM We develop truly individualized and patient-tailored treatments against cancer. Our objective is to transform cancer into a manageable and non-lethal disease by BioNTech’s initial product candidates for individualized cancer treatments providing treatments from a suite of therapeutic platforms and offering lifelong are developed using the company’s mRNA technology platform. The IVAC® patient support. We currently have several product candidates in clinical develop- (Individualized Vaccines Against Cancer) platform has enabled the design ment and have established all of the building blocks necessary in an effort to bring of immunotherapies targeting cancer mutations and therefore has the highly potent, tailor-made and individualized cancer therapies to patients. -
Mechanisms of HIV Protein Degradation Into Epitopes: Implications for Vaccine Design
Viruses 2014, 6, 3271-3292; doi:10.3390/v6083271 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Mechanisms of HIV Protein Degradation into Epitopes: Implications for Vaccine Design Marijana Rucevic †, Julie Boucau †, Jens Dinter †, Georgio Kourjian † and Sylvie Le Gall * Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, MA 02139, USA; E-Mails: [email protected] (M.R.); [email protected] (J.B.); [email protected] (J.D.); [email protected] (G.K.) † These authors contributed equally to this work. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-857-268-7010. Received: 11 June 2014; in revised form: 6 August 2014 / Accepted: 11 August 2014 / Published: 21 August 2014 Abstract: The degradation of HIV-derived proteins into epitopes displayed by MHC-I or MHC-II are the first events leading to the priming of HIV-specific immune responses and to the recognition of infected cells. Despite a wealth of information about peptidases involved in protein degradation, our knowledge of epitope presentation during HIV infection remains limited. Here we review current data on HIV protein degradation linking epitope production and immunodominance, viral evolution and impaired epitope presentation. We propose that an in-depth understanding of HIV antigen processing and presentation in relevant primary cells could be exploited to identify signatures leading to efficient or inefficient epitope presentation in HIV proteomes, and to improve the design of immunogens eliciting immune responses efficiently recognizing all infected cells. Keywords: HIV; antigen processing; protein degradation; proteasome; aminopeptidase; peptidase; immunogen; vaccine vector; dendritic cells; T cells; viral evolution Viruses 2014, 6 3272 1. -
Multi-Step Screening of Neoantigens'
www.nature.com/scientificreports OPEN Multi‑step screening of neoantigens’ HLA‑ and TCR‑interfaces improves prediction of survival Guilhem Richard1*, Anne S. De Groot2,3, Gary D. Steinberg4, Tzintzuni I. Garcia5, Alec Kacew5, Matthew Ardito2, William D. Martin2, Gad Berdugo1,6, Michael F. Princiotta1, Arjun V. Balar4 & Randy F. Sweis5* Improvement of risk stratifcation through prognostic biomarkers may enhance the personalization of cancer patient monitoring and treatment. We used Ancer, an immunoinformatic CD8, CD4, and regulatory T cell neoepitope screening system, to perform an advanced neoantigen analysis of genomic data derived from the urothelial cancer cohort of The Cancer Genome Atlas. Ancer demonstrated improved prognostic stratifcation and fve‑year survival prediction compared to standard analyses using tumor mutational burden or neoepitope identifcation using NetMHCpan and NetMHCIIpan. The superiority of Ancer, shown in both univariate and multivariate survival analyses, is attributed to the removal of neoepitopes that do not contribute to tumor immunogenicity based on their homology with self‑epitopes. This analysis suggests that the presence of a higher number of unique, non‑self CD8‑ and CD4‑neoepitopes contributes to cancer survival, and that prospectively defning these neoepitopes using Ancer is a novel prognostic or predictive biomarker. Understanding mechanisms of cancer progression and identifying patients at high risk for recurrence are pivotal to the personalization of cancer care. Improvements in DNA sequencing techniques combined with cost reduc- tions have enabled the routine mapping of the tumor genome and improved our mechanistic understanding of cancer progression and patients’ survival. Tumor mutational burden (TMB) has arisen as a potential cancer prognosis biomarker in numerous tumor types 1,2.