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Neoepitope and cancer

Rebecca A Evans, Mark S Diamond, Andrew J Rech, Timothy Chao, Max W Richardson, Jeffrey H Lin, David L Bajor, Katelyn T Byrne, Ben Z Stanger, James L Riley, Nune Markosyan, Rafael Winograd, Robert H Vonderheide
In carcinogen-driven cancers, a high mutational burden results in neoepitopes that can be recognized immunologically. Such carcinogen-induced tumors may evade this immune response through "immunoediting," whereby tumors adapt to immune pressure and escape T cell-mediated killing. Many tumors lack a high neoepitope burden, and it remains unclear whether immunoediting occurs in such cases. Here, we evaluated T cell immunity in an autochthonous mouse model of pancreatic cancer and found a low mutational burden, absence of predicted neoepitopes derived from tumor mutations, and resistance to checkpoint immunotherapy...
September 8, 2016: JCI Insight
David Gfeller, Michal Bassani-Sternberg, Julien Schmidt, Immanuel F Luescher
Tumor exome and RNA sequencing data provide a systematic and unbiased view on cancer-specific expression, over-expression, and mutations of genes, which can be mined for personalized cancer vaccines and other immunotherapies. Of key interest are tumor-specific mutations, because T cells recognizing neoepitopes have the potential to be highly tumoricidal. Here, we review recent developments and technical advances in identifying MHC class I and class II-restricted tumor antigens, especially neoantigen derived MHC ligands, including in silico predictions, immune-peptidome analysis by mass spectrometry, and MHC ligand validation by biochemical methods on T cells...
July 2016: Oncoimmunology
Roni Bareli, Cyrille J Cohen
Analysis of genomic data from patient tumors provides valuable information as to potential T-cell targets such as neoepitopes. We developed an approach to characterize, isolate and utilize neoantigens-specific T cells using MHC/peptide tetramers from fresh tumor digests and peripheral blood. This bears important implications for the implementation of T cell-based immunotherapy.
July 2016: Oncoimmunology
Amalie Kai Bentzen, Andrea Marion Marquard, Rikke Lyngaa, Sunil Kumar Saini, Sofie Ramskov, Marco Donia, Lina Such, Andrew J S Furness, Nicholas McGranahan, Rachel Rosenthal, Per Thor Straten, Zoltan Szallasi, Inge Marie Svane, Charles Swanton, Sergio A Quezada, Søren Nyboe Jakobsen, Aron Charles Eklund, Sine Reker Hadrup
Identification of the peptides recognized by individual T cells is important for understanding and treating immune-related diseases. Current cytometry-based approaches are limited to the simultaneous screening of 10-100 distinct T-cell specificities in one sample. Here we use peptide-major histocompatibility complex (MHC) multimers labeled with individual DNA barcodes to screen >1,000 peptide specificities in a single sample, and detect low-frequency CD8 T cells specific for virus- or cancer-restricted antigens...
October 2016: Nature Biotechnology
Tanner M Johanns, Jeffrey Ward, Courtney Wilson, Dale K Kobayashi, Diane Bender, Yujie Fu, Anton Alexandrov, Maxim N Artyomov, Chris A Miller, Elaine R Mardis, Gavin P Dunn
INTRODUCTION: Our understanding of how immune-based strategies designed to enhance T-cell activation might effectively control glioblastoma progression has been limited by our ability to identify and monitor tumor-specific T cells. The "cancer immunogenomics" approach has facilitated the search for tumor-specific antigens over the past 4 years by applying comprehensive cancer genomics to tumor antigen discovery. We applied this methodology to identify tumor-specific "neoantigens" in preclinical brain tumor models susceptible to checkpoint immunotherapy...
August 2016: Neurosurgery
Joshua D Campbell, Anton Alexandrov, Jaegil Kim, Jeremiah Wala, Alice H Berger, Chandra Sekhar Pedamallu, Sachet A Shukla, Guangwu Guo, Angela N Brooks, Bradley A Murray, Marcin Imielinski, Xin Hu, Shiyun Ling, Rehan Akbani, Mara Rosenberg, Carrie Cibulskis, Aruna Ramachandran, Eric A Collisson, David J Kwiatkowski, Michael S Lawrence, John N Weinstein, Roel G W Verhaak, Catherine J Wu, Peter S Hammerman, Andrew D Cherniack, Gad Getz, Maxim N Artyomov, Robert Schreiber, Ramaswamy Govindan, Matthew Meyerson
To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined the exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor-normal pairs. Recurrent alterations in lung SqCCs were more similar to those of other squamous carcinomas than to alterations in lung ADCs. New significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types...
June 2016: Nature Genetics
Maria J L Kracht, Arnaud Zaldumbide, Bart O Roep
Type 1 diabetes (T1D) is characterized by the selective and progressive destruction of insulin-producing beta cells by the immune system. An incomplete thymic selection against self-reactive islet antigens partly explains how these T cells reach the periphery and become diabetogenic. Increasing evidence suggest that beta cells themselves also participate to their own demise by generating neoepitopes that could be recognized by the immune surveillance machinery. In this regard, these T cells eradicate self-tissue by mechanisms analogous to a classical antitumor response...
June 2016: Trends in Endocrinology and Metabolism: TEM
Özlem Türeci, Mathias Vormehr, Mustafa Diken, Sebastian Kreiter, Christoph Huber, Ugur Sahin
Somatic mutations binding to the patient's MHC and recognized by autologous T cells (neoepitopes) are ideal cancer vaccine targets. They combine a favorable safety profile due to a lack of expression in healthy tissues with a high likelihood of immunogenicity, as T cells recognizing neoepitopes are not shaped by central immune tolerance. Proteins mutated in cancer (neoantigens) shared by patients have been explored as vaccine targets for many years. Shared ("public") mutations, however, are rare, as the vast majority of cancer mutations in a given tumor are unique for the individual patient...
April 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jonathan C Dudley, Ming-Tseh Lin, Dung T Le, James R Eshleman
Initial results by Le and colleagues, which were published in the June 25, 2015 issue of the New England Journal of Medicine, report significant responses of cancers with microsatellite instability (MSI) to anti-PD-1 inhibitors in patients who failed conventional therapy. This finding fits into a broader body of research associating somatic hypermutation and neoepitope formation with response to immunotherapy, with the added benefit of relying on a simple, widely used diagnostic test. This review surveys the pathogenesis and prognostic value of MSI, diagnostic guidelines for detecting it, and the frequency of MSI across tumors, with the goal of providing a reference for its use as a biomarker for PD-1 blockade...
February 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Alexander Jürets, Marie Le Bras, Günther Staffler, Gesine Stein, Lukas Leitner, Angelika Neuhofer, Matteo Tardelli, Edvin Turkof, Maximilian Zeyda, Thomas M Stulnig
Osteopontin (OPN), a secreted protein involved in inflammatory processes and cancer, induces cell adhesion, migration, and activation of inflammatory pathways in various cell types. Cells bind OPN via integrins at a canonical RGD region in the full length form as well as to a contiguous cryptic site that some have shown is unmasked upon thrombin or matrix metalloproteinase cleavage. Thus, the adhesive capacity of osteopontin is enhanced by proteolytic cleavage that may occur in inflammatory conditions such as obesity, atherosclerosis, rheumatoid arthritis, tumor growth and metastasis...
2016: PloS One
Ida Hafstrand, Elien M Doorduijn, Adil Doganay Duru, Jeremie Buratto, Claudia Cunha Oliveira, Tatyana Sandalova, Thorbald van Hall, Adnane Achour
MHC class I downregulation represents a significant challenge for successful T cell-based immunotherapy. T cell epitopes associated with impaired peptide processing (TEIPP) constitute a novel category of immunogenic Ags that are selectively presented on transporter associated with Ag processing-deficient cells. The TEIPP neoepitopes are CD8 T cell targets, derived from nonmutated self-proteins that might be exploited to prevent immune escape. In this study, the crystal structure of H-2D(b) in complex with the first identified TEIPP Ag (MCLRMTAVM) derived from the Trh4 protein has been determined to 2...
March 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Brooke E Howitt, Sachet A Shukla, Panagiotis A Konstantinopoulos
No abstract text is available yet for this article.
January 2016: JAMA Oncology
Inge C van Gool, Tjalling Bosse, David N Church
No abstract text is available yet for this article.
January 2016: JAMA Oncology
(no author information available yet)
Memorial Sloan Kettering Cancer Center has teamed up with biotechnology company Advaxis to explore development of neoepitope-based immunotherapies. The partnership is just one of several such ventures in a promising area of research that uses advanced sequencing technology to customize vaccines based on altered proteins in individual patients' tumors.
February 2016: Cancer Discovery
Daniele Mennonna, Cristina Maccalli, Michele C Romano, Claudio Garavaglia, Filippo Capocefalo, Roberta Bordoni, Marco Severgnini, Gianluca De Bellis, John Sidney, Alessandro Sette, Alessandro Gori, Renato Longhi, Marco Braga, Luca Ghirardelli, Ludovica Baldari, Elena Orsenigo, Luca Albarello, Elisabetta Zino, Katharina Fleischhauer, Gina Mazzola, Norma Ferrero, Antonio Amoroso, Giulia Casorati, Giorgio Parmiani, Paolo Dellabona
OBJECTIVE: Patient-specific (unique) tumour antigens, encoded by somatically mutated cancer genes, generate neoepitopes that are implicated in the induction of tumour-controlling T cell responses. Recent advancements in massive DNA sequencing combined with robust T cell epitope predictions have allowed their systematic identification in several malignancies. DESIGN: We undertook the identification of unique neoepitopes in colorectal cancers (CRCs) by using high-throughput sequencing of cDNAs expressed by standard cancer cell cultures, and by related cancer stem/initiating cells (CSCs) cultures, coupled with a reverse immunology approach not requiring human leukocyte antigen (HLA) allele-specific epitope predictions...
December 17, 2015: Gut
Sandra Van Lint, Dries Renmans, Katrijn Broos, Lode Goethals, Sarah Maenhout, Daphné Benteyn, Cleo Goyvaerts, Stephanie Du Four, Kevin Van der Jeught, Lukasz Bialkowski, Véronique Flamand, Carlo Heirman, Kris Thielemans, Karine Breckpot
Modulating the activity of tumor-infiltrating dendritic cells (TiDC) provides opportunities for novel cancer interventions. In this article, we report on our study of the uptake of mRNA by CD8α(+) cross-presenting TiDCs upon its intratumoral (i.t.) delivery. We exploited this property to deliver mRNA encoding the costimulatory molecule CD70, the activation stimuli CD40 ligand, and constitutively active Toll-like receptor 4, referred to as TriMix mRNA. We show that TiDCs are reprogrammed to mature antigen-presenting cells that migrate to tumor-draining lymph nodes (TDLN)...
February 2016: Cancer Immunology Research
Pramod K Srivastava
The search for specificity in cancers has been a holy grail in cancer immunology. Cancer geneticists have long known that cancers harbor transforming and other mutations. Immunologists have long known that inbred mice can be immunized against syngeneic cancers, indicating the existence of cancer-specific antigens. With the technological advances in high-throughput DNA sequencing and bioinformatics, the genetic and immunologic lines of inquiry are now converging to provide definitive evidence that human cancers are vastly different from normal tissues at the genetic level, and that some of these differences are recognized by the immune system...
September 2015: Cancer Immunology Research
Brooke E Howitt, Sachet A Shukla, Lynette M Sholl, Lauren L Ritterhouse, Jaclyn C Watkins, Scott Rodig, Elizabeth Stover, Kyle C Strickland, Alan D D'Andrea, Catherine J Wu, Ursula A Matulonis, Panagiotis A Konstantinopoulos
IMPORTANCE: Immune checkpoint inhibitor therapy has shown benefit in various cancers, but their potential in endometrial cancer (EC) is unknown. OBSERVATIONS: Prediction of neoantigen load was performed using sequencing data from the Cancer Genome Atlas data set. Evaluation of tumor-infiltrating lymphocytes (TILs) and PD-1 and PD-L1 expression was performed in 63 patients with EC referred to our institution. The predicted median (range) neoantigen load (predicted neoepitopes per sample) was proportional to the mutational load: highest in ultramutated polymerase e (POLE) tumors (8342 [628-20 440]), less in hypermutated MSI (541 [146-8063]; P < ...
December 2015: JAMA Oncology
Anna Polyakova, Ksenia Kuznetsova, Sergei Moshkovskii
Cancer proteogenomics is an emerging field that aims to identify and quantify protein sequence changes associated with the cancer genome. Besides being involved in cancer development and progression, such protein variants may serve as neoantigens, which provide the T-cell response against tumors. Mass spectrometry-based proteogenomics may be a promising tool for finding neoantigens in individual specimens. It is partly based on a technical background accumulated from mass spectrometric studies of peptide ligands of major histocompatibility complex proteins...
2015: Expert Review of Proteomics
J H Kristensen, L Larsen, B Dasgupta, C Brodmerkel, M Curran, M A Karsdal, J M B Sand, N Willumsen, A J Knox, C E Bolton, S R Johnson, P Hägglund, B Svensson, D J Leeming
OBJECTIVES: Elastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7 activity in regard to elastin degradation has never been quantified serologically in patients with lung diseases. An assay for the quantification of MMP-7 generated elastin fragments (ELM7) was therefore developed to investigate MMP-7 derived elastin degradation in pulmonary disorders such as idiopathic pulmonary fibrosis (IPF) and lung cancer...
November 2015: Clinical Biochemistry
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