Tumor Exome Analysis Reveals Neoantigen-Specific T-Cell Reactivity in an Ipilimumab-Responsive Melanoma

Rooij, Nienke van; Buuren, Marit M. van; Philips, Daisy; Velds, Arno; Toebes, Mireille; Heemskerk, Bianca; Dijk, Laura J. A. van; Behjati, Sam; Hilkmann, Henk; Atmioui, Dris El; Nieuwland, Marja; Stratton, Michael R.; Kerkhoven, Ron; Keşmir, Can; Haanen, John B.A.G.; Kvistborg, Pia; Schumacher, Ton N.

doi:10.1200/jco.2012.47.7521

Cited by 746 publications

(572 citation statements)

References 22 publications

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“…24,49 In this context, it is often mentioned that the tumor microenvironment plays a critical role for antitumor T cell responses, not only by inhibiting existing T cells, but also by preventing T cell priming against neoepitopes. 50,51 At the same time, it needs to be stressed that even in the context of e.g.…”

Section: Discussionmentioning

confidence: 99%

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%

Predicting T cell recognition of MHC class I restricted neoepitopes

et al. 2018

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“…Recently, the detection of T cells reacting against patient-specific mutated antigens has been related with clinical responses to IPI. [41][42][43] The determination of the repertoire of T cells reactive with both differentiation/cancer-testis and mutated TAAs along with the therapeutic usage of immunomodulatory agents need to be further dissected in MM patients. In addition, it is worthy to monitor T cell responses against tumor cells, which in our study represented a possible immunological parameter associated with the clinical outcome of patients.…”

Section: Discussionmentioning

confidence: 99%

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

Maccalli

Giannarelli²,

Capocefalo³

et al. 2015

OncoImmunology

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Moreover, either the absence or the presence of soluble NKG2D ligands (ULBP-1 or ¡2) at baseline in the serum of MM patients enabled to discriminate subjects with long-term survival (median overall survival, (OS) D 33.6 mo for ULBP-1 and ¡2) from poor survivors (OS D 9.8 or 6.6 mo, respectively). Conversely, no significant association between the levels of soluble MICA, MICB and ULBP-3 and the clinical outcome of patients was observed. An inverse correlation between circulating levels of these molecules at baseline and frequency of either CD3 C CD4 C CD45RO C BTLA C or Th17 or CD3 C CD4 C 4-1BB C T cells occurred in patients with a favorable clinical outcome. The simultaneous monitoring of different immune parameters, though validation in a large cohort of patients is needed, allowed to identify an association between phenotypic and soluble markers representing a possible predictive immunological signature for the clinical activity of IPI plus FTM.

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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%

Immune targets and neoantigens for cancer immunotherapy and precision medicine

2016

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Tumor Exome Analysis Reveals Neoantigen-Specific T-Cell Reactivity in an Ipilimumab-Responsive Melanoma

Abstract: The evidence for T-cell-mediated regression of human cancers such as non-small-cell lung carcinoma, renal cell carcinoma, and-in particular-melanoma after immunotherapy is

Cited by 746 publications

References 22 publications

Predicting T cell recognition of MHC class I restricted neoepitopes

Predicting T cell recognition of MHC class I restricted neoepitopes

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

Immune targets and neoantigens for cancer immunotherapy and precision medicine

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