scholarly journals pepsickle rapidly and accurately predicts proteasomal cleavage sites for improved neoantigen identification

2021 ◽  
Author(s):  
Benjamin R Weeder ◽  
Mary A Wood ◽  
Ellysia Li ◽  
Abhinav Nellore ◽  
Reid F Thompson
Keyword(s):  
Open Source ◽  
Antigen Processing ◽  
Vaccine Development ◽  
Epitope Prediction ◽  
Supplementary Information ◽  
Computational Speed ◽  
Post Hoc ◽  
Antigen Processing And Presentation ◽  
Proteasomal Cleavage

Abstract Motivation Proteasomal cleavage is a key component in protein turnover, as well as antigen processing and presentation. Although tools for proteasomal cleavage prediction are available, they vary widely in their performance, options, and availability. Results Herein we present pepsickle, an open-source tool for proteasomal cleavage prediction with better in vivo prediction performance (AUC) and computational speed than current models available in the field and with the ability to predict sites based on both constitutive and immunoproteasome profiles. Post-hoc filtering of predicted patient neoepitopes using pepsickle significantly enriches for immune-responsive epitopes and may improve current epitope prediction and vaccine development pipelines. Availability pepsickle is open source and available at https://github.com/pdxgx/pepsickle Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Pepsickle rapidly and accurately predicts proteasomal cleavage sites for improved neoantigen identification

2021 ◽  
Author(s):  
Benjamin Weeder ◽  
Mary Wood ◽  
Ellysia Li ◽  
Abhinav Nellore ◽  
Reid F Thompson
Keyword(s):  
Protein Turnover ◽  
Vaccine Development ◽  
Epitope Prediction ◽  
Prediction Performance ◽  
Cleavage Sites ◽  
Computational Speed ◽  
Post Hoc ◽  
Significant Opportunity ◽  
Proteasomal Cleavage

Proteasomal cleavage is a key component in protein turnover, as well as antigen presentation and subsequent immune response. Herein we present pepsickle, an open-source tool for proteasomal cleavage prediction with better in vivo prediction performance (AUC) and computational speed than current models available in the field, and with the ability to predict sites based on both constitutive and immunoproteasome profiles. Post-hoc filtering of predicted patient neoepitopes using pepsickle significantly enriches for immune-responsive epitopes and may represent a significant opportunity to improve current epitope prediction and vaccine development pipelines.

scholarly journals Inhibition of WHSC1 Allows for Reprogramming of the Immune Compartment in Prostate Cancer

2021 ◽  
Vol 22 (16) ◽  
pp. 8742
Author(s):  
Muzamil Y. Want ◽  
Ellen Karasik ◽  
Bryan Gillard ◽  
A. J. Robert McGray ◽  
Sebastiano Battaglia
Keyword(s):  
Prostate Cancer ◽  
Immune Responses ◽  
Antigen Processing ◽  
Single Cell Analysis ◽  
Cell Communication ◽  
Cell Analysis ◽  
Negative Results ◽  
Fundamental Understanding ◽  
Antigen Processing And Presentation

Immunotherapy initially demonstrated promising results in prostate cancer (PCa), but the modest or negative results of many recent trials highlight the need to overcome the poor immunogenicity of this cancer. The design of effective therapies for PCa is challenged by the limited understanding of the interface between PCa cells and the immune system in mediating therapeutic resistance. Prompted by our recent observations that elevated WHSC1, a histone methyltransferase known to promote progression of numerous cancers, can silence antigen processing and presentation in PCa, we performed a single-cell analysis of the intratumoral immune dynamics following in vivo pharmacological inhibition of WHSC1 in mice grafted with TRAMP C2 cells. We observed an increase in cytotoxic T and NK cells accumulation and effector function, accompanied by a parallel remodeling of the myeloid compartment, as well as abundant shifts in key ligand–receptor signaling pathways highlighting changes in cell-to-cell communication driven by WHSC1 inhibition. This comprehensive profiling of both immune and molecular changes during the course of WHSC1 blockade deepens our fundamental understanding of how anti-tumor immune responses develop and can be enhanced therapeutically for PCa.

scholarly journals Joint epitope selection and spacer design for string-of-beads vaccines

2020 ◽  
Vol 36 (Supplement_2) ◽  
pp. i643-i650
Author(s):  
Emilio Dorigatti ◽  
Benjamin Schubert
Keyword(s):  
Antigen Processing ◽  
State Of The Art ◽  
Supplementary Information ◽  
Current State ◽  
Fixed Set ◽  
Epitope Selection ◽  
High Chance ◽  
Selection Of ◽  
Design Steps

Abstract Motivation Conceptually, epitope-based vaccine design poses two distinct problems: (i) selecting the best epitopes to elicit the strongest possible immune response and (ii) arranging and linking them through short spacer sequences to string-of-beads vaccines, so that their recovery likelihood during antigen processing is maximized. Current state-of-the-art approaches solve this design problem sequentially. Consequently, such approaches are unable to capture the inter-dependencies between the two design steps, usually emphasizing theoretical immunogenicity over correct vaccine processing, thus resulting in vaccines with less effective immunogenicity in vivo. Results In this work, we present a computational approach based on linear programming, called JessEV, that solves both design steps simultaneously, allowing to weigh the selection of a set of epitopes that have great immunogenic potential against their assembly into a string-of-beads construct that provides a high chance of recovery. We conducted Monte Carlo cleavage simulations to show that a fixed set of epitopes often cannot be assembled adequately, whereas selecting epitopes to accommodate proper cleavage requirements substantially improves their recovery probability and thus the effective immunogenicity, pathogen and population coverage of the resulting vaccines by at least 2-fold. Availability and implementation The software and the data analyzed are available at https://github.com/SchubertLab/JessEV. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Region-specific transcriptomic and functional signatures of mononuclear phagocytes in the epididymis

2019 ◽  
Vol 26 (1) ◽  
pp. 14-29 ◽  
Author(s):  
Maria A Battistone ◽  
Alexandra C Mendelsohn ◽  
Raul German Spallanzani ◽  
Dennis Brown ◽  
Anil V Nair ◽  
...  
Keyword(s):  
Male Fertility ◽  
Antigen Processing ◽  
Inflammatory Responses ◽  
Mononuclear Phagocytes ◽  
Flow Cytometry Analysis ◽  
Close Proximity ◽  
In Vivo Labelling ◽  
Antigen Processing And Presentation ◽  
Immunoregulatory Mechanisms

Abstract In the epididymis, prevention of autoimmune responses against spermatozoa and simultaneous protection against pathogens is important for male fertility. We have previously shown that mononuclear phagocytes (MPs) are located either in the epididymal interstitium or in close proximity to the epithelium. In the initial segments (IS), these ‘intraepithelial’ MPs extend slender luminal-reaching projections between epithelial cells. In this study, we performed an in-depth characterisation of MPs isolated from IS, caput–corpus and cauda epididymis of CX3CR1EGFP+/− mice that express EGFP in these cells. Flow cytometry analysis revealed region-specific subsets of MPs that express combinations of markers traditionally described in ‘dendritic cells’ or ‘macrophages’. RNA sequencing identified distinct transcriptomic signatures in MPs from each region and revealed specific genes involved in inflammatory and anti-inflammatory responses, phagosomal activity and antigen processing and presentation. Functional fluorescent in vivo labelling assays showed that higher percentages of CX3CR1+ MPs that captured and processed antigens were detected in the IS compared to other regions. Confocal microscopy showed that in the IS, caput and corpus, circulatory antigens were internalised and processed by interstitial and intraepithelial MPs. However, in the cauda only interstitial MPs internalised and processed antigens, while intraepithelial MPs did not take up antigens, indicating that all antigens have been captured before they reached the epithelial lining. Cauda MPs may thus confer a stronger protection against blood-borne pathogens compared to proximal regions. By identifying immunoregulatory mechanisms in the epididymis, our study may lead to new therapies for male infertility and epididymitis and identify potential targets for immunocontraception.

scholarly journals Antigen processing and presentation in cancer immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001111 ◽  
Author(s):  
Maxwell Y Lee ◽  
Jun W Jeon ◽  
Cem Sievers ◽  
Clint T Allen
Keyword(s):  
T Cell ◽  
Mhc Class I ◽  
In Silico ◽  
Antigen Processing ◽  
Tumor Antigens ◽  
Epitope Prediction ◽  
Cell Tumor ◽  
Class I ◽  
Wide Range ◽  
Antigen Processing And Presentation

BackgroundKnowledge about and identification of T cell tumor antigens may inform the development of T cell receptor-engineered adoptive cell transfer or personalized cancer vaccine immunotherapy. Here, we review antigen processing and presentation and discuss limitations in tumor antigen prediction approaches.MethodsOriginal articles covering antigen processing and presentation, epitope discovery, and in silico T cell epitope prediction were reviewed.ResultsNatural processing and presentation of antigens is a complex process that involves proteasomal proteolysis of parental proteins, transportation of digested peptides into the endoplasmic reticulum, loading of peptides onto major histocompatibility complex (MHC) class I molecules, and shuttling of peptide:MHC complexes to the cell surface. A number of T cell tumor antigens have been experimentally validated in patients with cancer. Assessment of predicted MHC class I binding and total score for these validated T cell antigens demonstrated a wide range of values, with nearly one-third of validated antigens carrying an IC50 of greater than 500 nM.ConclusionsAntigen processing and presentation is a complex, multistep process. In silico epitope prediction techniques can be a useful tool, but comprehensive experimental testing and validation on a patient-by-patient basis may be required to reliably identify T cell tumor antigens.

scholarly journals Mannose 6 phosphorylation of lysosomal enzymes controls B cell functions

2015 ◽  
Vol 208 (2) ◽  
pp. 171-180 ◽  
Author(s):  
Takanobu Otomo ◽  
Michaela Schweizer ◽  
Katrin Kollmann ◽  
Valéa Schumacher ◽  
Nicole Muschol ◽  
...  
Keyword(s):  
B Cell ◽  
Antigen Processing ◽  
Lysosomal Enzymes ◽  
Intracellular Transport ◽  
Critical Role ◽  
Significant Loss ◽  
Cell Functions ◽  
Dependent Transport ◽  
Antigen Processing And Presentation

Antigen processing and presentation and cytotoxic targeting depend on the activities of several lysosomal enzymes that require mannose 6-phosphate (M6P) sorting signals for efficient intracellular transport and localization. In this paper, we show that mice deficient in the formation of M6P residues exhibit significant loss of cathepsin proteases in B cells, leading to lysosomal dysfunction with accumulation of storage material, impaired antigen processing and presentation, and subsequent defects in B cell maturation and antibody production. The targeting of lysosomal and granular enzymes lacking M6P residues is less affected in dendritic cells and T cells and sufficient for maintenance of degradative and lytic functions. M6P deficiency also impairs serum immunoglobulin levels and antibody responses to vaccination in patients. Our data demonstrate the critical role of M6P-dependent transport routes for B cell functions in vivo and humoral immunity in mice and human.

scholarly journals Design of T cell epitope-based vaccine candidate for SARS-CoV-2 targeting nucleocapsid and spike protein escape variants

2021 ◽  
Author(s):  
Gabriel Jabbour ◽  
Samantha Rego ◽  
Vincent Nguyenkhoa ◽  
Sivanesan Dakshanamurthy
Keyword(s):  
T Cell ◽  
Vaccine Development ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
T Cell Epitopes ◽  
Clinical Predictors ◽  
Nucleocapsid Proteins ◽  
Global Concern

AbstractThe current COVID-19 pandemic continues to spread and devastate in the absence of effective treatments, warranting global concern and action. Despite progress in vaccine development, the rise of novel, increasingly infectious SARS-CoV-2 variants makes it clear that our response to the virus must continue to evolve along with it. The use of immunoinformatics provides an opportunity to rapidly and efficiently expand the tools at our disposal to combat the current pandemic and prepare for future outbreaks through epitope-based vaccine design. In this study, we validated and compared the currently available epitope prediction tools, and then used the best tools to predict T cell epitopes from SARS-CoV-2 spike and nucleocapsid proteins for use in an epitope-based vaccine. We combined the mouse MHC affinity predictor and clinical predictors such as HLA affinity, immunogenicity, antigenicity, allergenicity, toxicity and stability to select the highest quality CD8 and CD4 T cell epitopes for the common SARS-CoV-2 variants of concern suitable for further preclinical studies. We also identified variant-specific epitopes to more precisely target the Alpha, Beta, Gamma, Delta, Cluster 5 and US variants. We then modeled the 3D structures of our top 4 N and S epitopes to investigate the molecular interaction between peptide-MHC and peptide-MHC-TCR complexes. Following in vitro and in vivo validation, the epitopes identified by this study may be used in an epitope-based vaccine to protect across all current variants, as well as in variant-specific booster shots to target variants of concern. Immunoinformatics tools allowed us to efficiently predict epitopes in silico most likely to prove effective in vivo, providing a more streamlined process for vaccine development in the context of a rapidly evolving pandemic.

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