[citation report] Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells

Cited by 968 publications

(840 citation statements)

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“…most are not immunogenic. 24,28,46 Especially in patients with high mutational load, hundreds or even thousands of mutated peptides are commonly found based on sequencing approaches, highlighting the need to further narrow down this candidate list and increase the specificity in detecting immunogenic neoepitopes.…”

Section: Discussionmentioning

confidence: 99%

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Predicting T cell recognition of MHC class I restricted neoepitopes

et al. 2018

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Epitopes that arise from a somatic mutation, also called neoepitopes, are now known to play a key role in cancer immunology and immunotherapy. Recent advances in high-throughput sequencing have made it possible to identify all mutations and thereby all potential neoepitope candidates in an individual cancer. However, most of these neoepitope candidates are not recognized by T cells of cancer patients when tested in vivo or in vitro, meaning they are not immunogenic. Especially in patients with a high mutational load, usually hundreds of potential neoepitopes are detected, highlighting the need to further narrow down this candidate list. In our study, we assembled a dataset of known, naturally processed, immunogenic neoepitopes to dissect the properties that make these neoepitopes immunogenic. The tools to use and thresholds to apply for prioritizing neoepitopes have so far been largely based on experience with epitope identification in other settings such as infectious disease and allergy. Here, we performed a detailed analysis on our dataset of curated immunogenic neoepitopes to establish the appropriate tools and thresholds in the cancer setting. To this end, we evaluated different predictors for parameters that play a role in a neoepitope’s immunogenicity and suggest that using binding predictions and length-rescaling yields the best performance in discriminating immunogenic neoepitopes from a background set of mutated peptides. We furthermore show that almost all neoepitopes had strong predicted binding affinities (as expected), but more surprisingly, the corresponding non-mutated peptides had nearly as high affinities. Our results provide a rational basis for parameters in neoepitope filtering approaches that are being commonly used.Abbreviations: SNV: single nucleotide variant; nsSNV: nonsynonymous single nucleotide variant; ROC: receiver operating characteristic; AUC: area under ROC curve; HLA: human leukocyte antigen; MHC: major histocompatibility complex; PD-1: Programmed cell death protein 1; PD-L1 or CTLA-4: cytotoxic T-lymphocyte associated protein 4

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Section: Discussionmentioning

confidence: 99%

“…Several of the peptides from the NCI dataset were also published, 46,61–63 which resulted in an overlap with the curated literature dataset. To keep the datasets distinct from each other, we filtered the literature dataset and removed all peptides included in the NCI dataset for all bioinformatics and statistical analyses.…”

Section: Methodsmentioning

confidence: 99%

Predicting T cell recognition of MHC class I restricted neoepitopes

et al. 2018

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“…These studies demonstrate that neoantigens can be rapidly identified within a few weeks and can serve as tumor-specific targets for T cell-mediated recognition and destruction of tumor cells. Similarly, several neoantigens have been identified from human cancer recognized by CD8 + and CD4 + T cells through exome sequencing and screening for T cell responses [221][222][223]. More recently, it has been further demonstrated that neoantigen-specific T cells can be isolated from patient PBMCs using FACS analysis and purification, although their frequencies are much lower than neoantigen-specific T cells in the corresponding TIL populations [45,224].…”

Section: The Second Wave Of Tumor Antigen Discovery: Mutation-derivedmentioning

confidence: 99%

“…In subsequent validation steps, tumor-reactive T cells are the key to screening and identification of T cell-recognized neoantigens (Table 3). TILs can be isolated from freshly obtained tumor tissues and used for screening candidate neoantigens [221]. Alternatively, neoantigen-specific T cells may be isolated from the patient's PBMCs based on upregulation of activation markers such as 4-1BB, OX-40 and PD-1 on T cells [224,235].…”

Section: Identifying Neoantigens Recognized By Cd8 + T Cellsmentioning

confidence: 99%

Immune targets and neoantigens for cancer immunotherapy and precision medicine

2016

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“…First, in-depth evaluation of the T-cell response in melanoma patients who responded to TIL-therapy, and infusion of ex vivo expanded tumor-infiltrating T cells, revealed that the T-cell clones driving therapeutic efficacy were not directed against lineage-specific and cancer testis antigens, but instead against neo-epitopes encoded by the tumor mutanome [3]. Essentially the same observation was subsequently made in patients responding to so-called checkpoint inhibitors, antibodies against cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) or the programmed cell death (PD)-1/PD-L1 axis, that can activate T cells by neutralizing inhibitory pathways in T cells [4].…”

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confidence: 99%