Neoepitopes as Difference Makers for General Cancer Vaccines?
Ontology highlight
ABSTRACT:
SUBMITTER: Filderman JN
PROVIDER: S-EPMC7484287 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Publications
Neoepitopes as Difference Makers for General Cancer Vaccines?
Filderman Jessica N JN Storkus Walter J WJ
Clinical cancer research : an official journal of the American Association for Cancer Research 20200709 17
The cancer mutanome has been associated with disease prognosis as well as response to interventional immunotherapy and provides a substrate for development of personalized vaccines targeting tumor neoepitopes. Recent findings suggest that neoantigen-based vaccines may represent general interventional approaches for patients with solid cancers, regardless of their inherent mutational burden.<i>See related article by Fang et al., p. 4511</i>. ...[more]
Similar Datasets
Project description:Somatic variations are frequent and important drivers in cancers. Amino acid substitutions can yield neoantigens that are detected by the immune system. Neoantigens can lead to immune response and tumor rejection. Although neoantigen load and occurrence have been widely studied, a detailed pan-cancer analysis of the occurrence and characterization of neoepitopes is missing. We investigated the proteome-wide amino acid substitutions in 8-, 9-, 10-, and 11-mer peptides in 30 cancer types with the NetMHC 4.0 software. 11,316,078 (0.24%) of the predicted 8-, 9-, 10-, and 11-mer peptides were highly likely neoepitope candidates and were derived from 95.44% of human proteins. Binding affinity to MHC molecules is just one of the many epitope features. The most likely epitopes are those which are detected by several MHCs and of several peptide lengths. 9-mer peptides are the most common among the high binding neoantigens. 0.17% of all variants yield more than 100 neoepitopes and are considered as the best candidates for any application. Amino acid distributions indicate that variants at all positions in neoepitopes of any length are, on average, more hydrophobic than the wild-type residues. We characterized properties of neoepitopes in 30 cancer types and estimated the likely numbers of tumor-derived epitopes that could induce an immune response. We found that amino acid distributions, at all positions in neoepitopes of all lengths, contain more hydrophobic residues than the wild-type sequences implying that the hydropathy nature of neoepitopes is an important property. The neoepitope characteristics can be employed for various applications including targeted cancer vaccine development for precision medicine.
| S-EPMC6109115 | biostudies-literature
Project description:We present an in silico approach to identifying neoepitopes derived from intron retention events in tumor transcriptomes. Using mass spectrometry immunopeptidome analysis, we show that retained intron neoepitopes are processed and presented on MHC I on the surface of cancer cell lines. RNA-derived neoepitopes should be considered for prospective personalized cancer vaccine development.
| S-EPMC6226333 | biostudies-literature
Project description:BACKGROUND:Tumor neoantigens are drivers of cancer immunotherapy response; however, current prediction tools produce many candidates requiring further prioritization. Additional filtration criteria and population-level understanding may assist with prioritization. Herein, we show neoepitope immunogenicity is related to measures of peptide novelty and report population-level behavior of these and other metrics. METHODS:We propose four peptide novelty metrics to refine predicted neoantigenicity: tumor vs. paired normal peptide binding affinity difference, tumor vs. paired normal peptide sequence similarity, tumor vs. closest human peptide sequence similarity, and tumor vs. closest microbial peptide sequence similarity. We apply these metrics to neoepitopes predicted from somatic missense mutations in The Cancer Genome Atlas (TCGA) and a cohort of melanoma patients, and to a group of peptides with neoepitope-specific immune response data using an extension of pVAC-Seq (Hundal et al., pVAC-Seq: a genome-guided in silico approach to identifying tumor neoantigens. Genome Med 8:11, 2016). RESULTS:We show neoepitope burden varies across TCGA diseases and HLA alleles, with surprisingly low repetition of neoepitope sequences across patients or neoepitope preferences among sets of HLA alleles. Only 20.3% of predicted neoepitopes across TCGA patients displayed novel binding change based on our binding affinity difference criteria. Similarity of amino acid sequence was typically high between paired tumor-normal epitopes, but in 24.6% of cases, neoepitopes were more similar to other human peptides, or bacterial (56.8% of cases) or viral peptides (15.5% of cases), than their paired normal counterparts. Applied to peptides with neoepitope-specific immune response, a linear model incorporating neoepitope binding affinity, protein sequence similarity between neoepitopes and their closest viral peptides, and paired binding affinity difference was able to predict immunogenicity (AUROC?=?0.66). CONCLUSIONS:Our proposed prioritization criteria emphasize neoepitope novelty and refine patient neoepitope predictions for focus on biologically meaningful candidate neoantigens. We have demonstrated that neoepitopes should be considered not only with respect to their paired normal epitope, but to the entire human proteome, and bacterial and viral peptides, with potential implications for neoepitope immunogenicity and personalized vaccines for cancer treatment. We conclude that putative neoantigens are highly variable across individuals as a function of cancer genetics and personalized HLA repertoire, while the overall behavior of filtration criteria reflects predictable patterns.
| S-EPMC5899330 | biostudies-literature
Project description:MHC I-restricted epitopes of chicken ovalbumin (OVA) were originally identified using CD8 T cells as probes. Here, using bioinformatics tools, we identify four additional epitopes in OVA in addition to a cryptic epitope. Each new epitope is presented in vivo, as deduced from the lack of CD8 response to it in OVA-transgenic mice. In addition, CD8 responses to the known and novel epitopes are examined in C57BL/6 mice exposed to the OVA-expressing tumor E.G7 in several ways. No responses to any epitope including SIINFEKL are detected in mice with growing E.G7 or mice immunized with the tumor. Only in E.G7-bearing mice treated with an anti-CTLA4 antibody which depletes tumor-infiltrating regulatory T cells, CD8 responses to SIINFEKL and the novel epitope EKYNLTSVL are detected. Finally, all epitopes fails to treat mice with pre-existing tumors. These observations force an important re-consideration of the common assumptions about the therapeutic value of neoepitopes detected by CD8 responses in tumor-bearing hosts.
| S-EPMC6538383 | biostudies-literature
Project description:Aberrantly truncated immature O-glycosylation in proteins occurs in essentially all types of epithelial cancer cells, which was demonstrated to be a common feature of most adenocarcinomas and strongly associated with cancer proliferation and metastasis. Although extensive efforts have been made toward the development of anticancer antibodies targeting MUC1, one of the most studied mucins having cancer-relevant immature O-glycans, no anti-MUC1 antibody recognises carbohydrates and the proximal MUC1 peptide region, concurrently. Here we present a general strategy that allows for the creation of antibodies interacting specifically with glycopeptidic neoepitopes by using homogeneous synthetic MUC1 glycopeptides designed for the streamlined process of immunization, antibody screening, three-dimensional structure analysis, epitope mapping and biochemical analysis. The X-ray crystal structure of the anti-MUC1 monoclonal antibody SN-101 complexed with the antigenic glycopeptide provides for the first time evidence that SN-101 recognises specifically the essential epitope by forming multiple hydrogen bonds both with the proximal peptide and GalNAc linked to the threonine residue, concurrently. Remarkably, the structure of the MUC1 glycopeptide in complex with SN-101 is identical to its solution NMR structure, an extended conformation induced by site-specific glycosylation. We demonstrate that this method accelerates dramatically the development of a new class of designated antibodies targeting a variety of "dynamic neoepitopes" elaborated by disease-specific O-glycosylation in the immunodominant mucin domains and mucin-like sequences found in intrinsically disordered regions of many proteins.
| S-EPMC8159228 | biostudies-literature
Project description:Neoepitopes have attracted much attention as targets for immunotherapy against cancer. Therefore, efficient neoepitope screening technology is an essential step in the development of personalized vaccines. Circular RNAs (circRNAs) are generated by back-splicing and have a single-stranded continuous circular structure. So far, various circRNAs have been poorly characterized, though new evidence suggests that a few translated circRNAs may play a role in cancer. In the present study, circRNA was used as a source of neoepitope, a novel strategy as circRNA-derived neoepitopes have never been previously explored. The present study reports CIRC_neo (circRNA-derived neoepitope prediction pipeline), which is a comprehensive and automated bioinformatic pipeline for the prediction of circRNA-derived neoepitopes from RNA sequencing data. The computational prediction from sequencing data requires complex computational workflows to identify circRNAs, derive the resulting peptides, infer the types of human leukocyte antigens (HLA I and HLA II) in patients, and predict the neoepitopes binding to these antigens. The present study proposes a novel source of neoepitopes. The study focused on cancer-specific circRNAs, which have greatly expanded the source pool for neoepitope discovery. The statistical analysis of different features of circRNA-derived neoepitopes revealed that circRNAs could produce long proteins or truncated proteins. Because the peptides were completely foreign to the human body, they could be highly immunogenic. Importantly, circRNA-derived neoepitopes capable of binding to HLA were discovered. In the current study, circRNAs were systematically analyzed, revealing potential targets and novel research clues for cancer diagnosis, treatment, and prospective personalized vaccine research.
| S-EPMC10130363 | biostudies-literature
Project description:Neoantigen tumor vaccines have shown promising anti-tumor efficacy in early clinical trials. However, the underlying mechanism regarding response or resistance to this treatment remains unclear. Therefore, further studies using advanced technologies such as single-cell RNA sequencing (scRNA-seq) were performed to reveal significant changes in tumor microenvironment after vaccination.
2024-04-21 | GSE264082 | GEO
Project description:Exitron splicing (EIS) creates a cryptic intron (called an exitron) within a protein-coding exon to increase proteome diversity. EIS is poorly characterized, but emerging evidence suggests a role for EIS in cancer. Through a systematic investigation of EIS across 33 cancers from 9,599 tumor transcriptomes, we discovered that EIS affected 63% of human coding genes and that 95% of those events were tumor specific. Notably, we observed a mutually exclusive pattern between EIS and somatic mutations in their affected genes. Functionally, we discovered that EIS altered known and novel cancer driver genes for causing gain- or loss-of-function, which promotes tumor progression. Importantly, we identified EIS-derived neoepitopes that bind to major histocompatibility complex (MHC) class I or II. Analysis of clinical data from a clear cell renal cell carcinoma cohort revealed an association between EIS-derived neoantigen load and checkpoint inhibitor response. Our findings establish the importance of considering EIS alterations when nominating cancer driver events and neoantigens.
| S-EPMC8141048 | biostudies-literature
Project description:Identification of neoepitopes that are effective in cancer therapy is a major challenge in creating cancer vaccines. Here, using an entirely unbiased approach, we queried all possible neoepitopes in a mouse cancer model and asked which of those are effective in mediating tumor rejection and, independently, in eliciting a measurable CD8 response. This analysis uncovered a large trove of effective anticancer neoepitopes that have strikingly different properties from conventional epitopes and suggested an algorithm to predict them. It also revealed that our current methods of prediction discard the overwhelming majority of true anticancer neoepitopes. These results from a single mouse model were validated in another antigenically distinct mouse cancer model and are consistent with data reported in human studies. Structural modeling showed how the MHC I-presented neoepitopes had an altered conformation, higher stability, or increased exposure to T cell receptors as compared with the unmutated counterparts. T cells elicited by the active neoepitopes identified here demonstrated a stem-like early dysfunctional phenotype associated with effective responses against viruses and tumors of transgenic mice. These abundant anticancer neoepitopes, which have not been tested in human studies thus far, can be exploited for generation of personalized human cancer vaccines.
| S-EPMC7843235 | biostudies-literature
Project description:Personal Neoantigen Cancer Vaccines
| PRJNA401959 | ENA