Factoring in Antigen Processing in Designing Antitumor T-Cell Vaccines

2008 ◽  
pp. 1-30
Author(s):  
Frédéric Lévy ◽  
Sara Colombetti ◽  
Jozef Janda ◽  
Laurence Chapatte ◽  
Pedro Alves ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Processing

scholarly journals Cross-presentation of a TAP-independent signal peptide induces CD8 T immunity to escaped cancers but necessitates anchor replacement

2021 ◽  
Author(s):  
Koen A. Marijt ◽  
Lisa Griffioen ◽  
Laura Blijleven ◽  
Sjoerd. H. van der Burg ◽  
Thorbald van Hall
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Signal Sequence ◽  
Cell Repertoire ◽  
Cross Presentation ◽  
Normal Tissues ◽  
Cell Immunity

AbstractCancer cells frequently display defects in their antigen-processing pathway and thereby evade CD8 T cell immunity. We described a novel category of cancer antigens, named TEIPP, that emerge on cancers with functional loss of the peptide pump TAP. TEIPPs are non-mutated neoantigens despite their ‘self’ origin by virtue of their absence on normal tissues. Here, we describe the development of a synthetic long peptide (SLP) vaccine for the most immunogenic TEIPP antigen identified thus far, derived from the TAP-independent LRPAP1 signal sequence. LRPAP121–30-specific CD8 T cells were present in blood of all tested healthy donors as well as patients with non-small cell lung adenocarcinoma. SLPs with natural flanking, however, failed to be cross-presented by monocyte-derived dendritic cells. Since the C-terminus of LRPAP121–30 is an unconventional and weakly binding serine (S), we investigated if replacement of this anchor would result in efficient cross-presentation. Exchange into a valine (V) resulted in higher HLA-A2 binding affinity and enhanced T cell stimulation. Importantly, CD8 T cells isolated using the V-variant were able to bind tetramers with the natural S-variant and respond to TAP-deficient cancer cells. A functional screen with an array of N-terminal and C-terminal extended SLPs pointed at the 24-mer V-SLP, elongated at the N-terminus, as most optimal vaccine candidate. This SLP was efficiently cross-presented and consistently induced a strong polyclonal LRPAP121–30-specific CD8 T cells from the endogenous T cell repertoire. Thus, we designed a TEIPP SLP vaccine from the LRPAP1 signal sequence ready for validation in clinical trials.

scholarly journals CD8+ T Cells Involved in Metabolic Inflammation in Visceral Adipose Tissue and Liver of Transgenic Pigs

2021 ◽  
Vol 12 ◽  
Author(s):  
Kaiyi Zhang ◽  
Cong Tao ◽  
Jianping Xu ◽  
Jinxue Ruan ◽  
Jihan Xia ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
T Cell ◽  
Visceral Adipose Tissue ◽  
Antigen Processing ◽  
Metabolic Diseases ◽  
Early Stage ◽  
Large Animal ◽  
Transgenic Pigs ◽  
Inflammatory Signaling ◽  
Visceral Adipose

Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, GIPRdn, hIAPP and PNPLA3I148M. Transgenic effect increased the risk of metabolic disorders. Triple-transgenic pigs with short-term diet intervention showed early symptoms of type 2 diabetes, including glucose intolerance, pancreatic lipid infiltration, islet hypertrophy, hepatic lobular inflammation and adipose tissue inflammation. Molecular pathways related to CD8+ T cell function were significantly activated in the liver and visceral adipose samples from triple-transgenic pigs, including antigen processing and presentation, T-cell receptor signaling, co-stimulation, cytotoxicity, and cytokine and chemokine secretion. The similar pro-inflammatory signaling in liver and visceral adipose tissue indicated that there might be a potential immune crosstalk between the two tissues. Moreover, genes that functionally related to liver antioxidant activity, mitochondrial function and extracellular matrix showed distinct expression between the two groups, indicating metabolic stress in transgenic pigs’ liver samples. We confirmed that triple-transgenic pigs had high coincidence with human metabolic diseases, especially in the scope of inflammatory signaling at early stage metaflammation. Taken together, this study provides a valuable large animal model for the clinical study of metaflammation and metabolic diseases.

scholarly journals CD4+ Th immunogenicity of the Ascaris spp. secreted products

2019 ◽  
Author(s):  
Friederike Ebner ◽  
Eliot Morrison ◽  
Miriam Bertazzon ◽  
Ankur Midha ◽  
Susanne Hartmann ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Processing ◽  
Cell Epitope ◽  
Processing System ◽  
Healthy Human ◽  
Major Health Problem ◽  
Major Health ◽  
T Cell Lines

SummaryAscaris spp. is a major health problem of humans and animals alike, and understanding the immunogenicity of its antigens is required for developing urgently needed vaccines. The parasite-secreted products represent the most relevant, yet highly complex (>250 proteins) antigens of Ascaris spp. as defining the pathogen-host interplay. We applied an in vitro antigen processing system coupled to quantitative proteomics to identify potential CD4+ Th cell epitopes in Ascaris suum-secreted products. This approach restricts the theoretical list of epitopes, based on affinity prediction, by a factor of ∼1200. More importantly, selection of 2 candidate peptides based on experimental evidence demonstrated the presence of epitope-reactive T cells in Ascaris-specific T cell lines generated from healthy human individuals. Thus, this stringent work pipeline identifies a human haplotype-specific T cell epitope of a major human pathogen. The methodology described represents an easily adaptable platform for characterization of highly complex pathogenic antigens and their MHCII-restriction.

scholarly journals INeo-Epp: A novel T-cell HLA class-I immunogenicity or neoantigenic epitope prediction method based on sequence related amino acid features

2019 ◽  
Author(s):  
Guangzhi Wang ◽  
Huihui Wan ◽  
Xingxing Jian ◽  
Yuyu Li ◽  
Jian Ouyang ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
Antigen Processing ◽  
External Validation ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
Validation Data ◽  
Data Set ◽  
Immunogenic Peptide ◽  
Related Amino Acid

AbstractIn silico T-cell epitope prediction plays an important role in immunization experimental design and vaccine preparation. Currently, most epitope prediction research focuses on peptide processing and presentation, e.g. proteasomal cleavage, transporter associated with antigen processing (TAP) and major histocompatibility complex (MHC) combination. To date, however, the mechanism for immunogenicity of epitopes remains unclear. It is generally agreed upon that T-cell immunogenicity may be influenced by the foreignness, accessibility, molecular weight, molecular structure, molecular conformation, chemical properties and physical properties of target peptides to different degrees. In this work, we tried to combine these factors. Firstly, we collected significant experimental HLA-I T-cell immunogenic peptide data, as well as the potential immunogenic amino acid properties. Several characteristics were extracted, including amino acid physicochemical property of epitope sequence, peptide entropy, eluted ligand likelihood percentile rank (EL rank(%)) score and frequency score for immunogenic peptide. Subsequently, a random forest classifier for T cell immunogenic HLA-I presenting antigen epitopes and neoantigens was constructed. The classification results for the antigen epitopes outperformed the previous research (the optimal AUC=0.81, external validation data set AUC=0.77). As mutational epitopes generated by the coding region contain only the alterations of one or two amino acids, we assume that these characteristics might also be applied to the classification of the endogenic mutational neoepitopes also called ‘neoantigens’. Based on mutation information and sequence related amino acid characteristics, a prediction model of neoantigen was established as well (the optimal AUC=0.78). Further, an easy-to-use web-based tool ‘INeo-Epp’ was developed (available at http://www.biostatistics.online/INeo-Epp/neoantigen.php)for the prediction of human immunogenic antigen epitopes and neoantigen epitopes.

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