Gene fusion neoantigens: Emerging targets for cancer immunotherapy

Wang, Yue; Shi, Tao; Song, Xueru; Liu, Baorui; Wei, Jia

doi:10.1016/j.canlet.2021.02.023

Cited by 55 publications

(58 citation statements)

References 63 publications

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“…Given the fact that high SNV or indel mutational burdens are limited, especially in pediatric malignancies, the repertoire of tumor antigens needs to be broadened [ 12 ]. Several clinical studies are currently evaluating immunotherapy in medulloblastoma [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, fusion proteins can be a result of RNA-dysregulation events like noncanonical splicing, in which fusion transcripts can be generated from trans -splicing [ 10 ]. In the context of immunotherapy, tumor-specific antigens resulting from gene fusions tend to be more immunogenic than classical neoantigens resulting from single nucleotide variants (SNV) or indels (insertion or deletion) [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1

Paret

Lehmann

Bender

et al. 2021

Cancers

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Medulloblastoma is the most common malignant brain tumor in children. Immunotherapy is yet to demonstrate dramatic results in medulloblastoma, one reason being the low rate of mutations creating new antigens in this entity. In tumors with low mutational burden, gene fusions may represent a source of tumor-specific neoantigens. Here, we reviewed the landscape of fusions in medulloblastoma and analyzed their predicted immunogenicity. Furthermore, we described a new in-frame fusion protein identified by RNA-Seq. The fusion involved two genes on chromosome 2 coding for the enhancer of polycomb homolog 2 (EPC2) and GULP PTB domain containing engulfment adaptor 1 (GULP1) respectively. By qRT-PCR analysis, the fusion was detected in 3 out of 11 medulloblastoma samples, whereby 2 samples were from the same patients obtained at 2 different time points (initial diagnosis and relapse), but not in other pediatric brain tumor entities. Cloning of the full-length sequence indicated that the fusion protein contains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 and the coiled-coil domain of GULP1. In silico analyses predicted binding of the neoantigen-derived peptide to HLA-A*0201. A total of 50% of the fusions described in the literature were also predicted to produce an immunogenic peptide. The EPC2-GULP1 fusion peptide was able to induce a de novo T cell response characterized by interferon gamma release of CD8+ cytotoxic T cells in vitro. While the functional relevance of this fusion in medulloblastoma biology remains to be clarified, our data support an immunotherapeutic approach for pediatric medulloblastoma patients carrying the EPC2-GULP1 fusion and other immunogenic fusions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1

Paret

Lehmann

Bender

et al. 2021

Cancers

View full text Add to dashboard Cite

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“…These foreign proteins are naturally processed by antigen-presenting cells (APC) cells and presented by human leukocyte antigens (HLAs) and then truly induce an efficient response of CD8 + T or CD4 + T lymphocytes ( 6 – 8 ). Theoretically, tumor neoantigens are promising cancer immunotherapy targets due to being not subject to central tolerance and less likely trigger autoimmune toxicity ( 7 , 9 – 11 ).…”

Section: Introductionmentioning

confidence: 99%

“…Integrating with next-generation sequencing, this approach has reported dozens of neoantigens deriving from immunopeptidomic analysis ( 22 – 25 ). In addition, fusion is an important class of somatic mutations formed by chromosome structural variation (SV) ( 11 ), which can serve as an ideal source of neoantigens for creating an open reading frame (ORF) ( 11 , 26 , 27 ). Wei et al.…”

Section: Introductionmentioning

confidence: 99%

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dbPepNeo2.0: A Database for Human Tumor Neoantigen Peptides From Mass Spectrometry and TCR Recognition

Jian

et al. 2022

Front. Immunol.

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Neoantigens are widely reported to induce T-cell response and lead to tumor regression, indicating a promising potential to immunotherapy. Previously, we constructed an open-access database, i.e., dbPepNeo, providing a systematic resource for human tumor neoantigens to storage and query. In order to expand data volume and application scope, we updated dbPepNeo to version 2.0 (http://www.biostatistics.online/dbPepNeo2). Here, we provide about 801 high-confidence (HC) neoantigens (increased by 170%) and 842,289 low-confidence (LC) HLA immunopeptidomes (increased by 107%). Notably, 55 class II HC neoantigens and 630 neoantigen-reactive T-cell receptor-β (TCRβ) sequences were firstly included. Besides, two new analytical tools are developed, DeepCNN-Ineo and BLASTdb. DeepCNN-Ineo predicts the immunogenicity of class I neoantigens, and BLASTdb performs local alignments to look for sequence similarities in dbPepNeo2.0. Meanwhile, the web features and interface have been greatly improved and enhanced.

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The characteristics and clinical relevance of tumor fusion burden in head and neck squamous cell carcinoma

Ren

et al. 2022

Cancer Medicine

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Background Recent studies suggest that tumor fusion burden (TFB) is a hallmark of immune infiltration in prostate cancer, the correlation of TFB with immune microenvironment, and genomic patterns in head and neck squamous cell carcinomas (HNSC) remain largely unclear. Methods Gene fusion, genomic, transcriptomic, and clinical data of HNSC patients from the cancer genome atlas (TCGA) database were collected to analyze the correlation of TFB with mutation patterns, tumor immune microenvironment, and survival time in HNSC patients. Results Human papillomavirus (HPV) (−) patients with low TFB exhibited significantly enhanced CD8+ T cells infiltration and cytolysis activity and increased level of interferon‐gamma (IL‐γ), human leukocyte antigen (HLA) class I, and chemokines. Moreover, TFB was positively correlated with TP53 mutation, score of gene copy number, and loss of heterozygosity (LOH), as well as the biological progress of epithelial‐mesenchymal transition (EMT), metastasis, and stem cell characteristics. Further analysis revealed that HPV (−) HNSC patients with low TFB have a better prognosis. Conclusions Our data revealed the correlation of TFB with tumor immune microenvironment and predictive features for immunotherapy, implying tumors with low TFB may be potential candidates for immunotherapeutic agents. Moreover, the TFB low group had prolonged overall survival (OS) in the HPV (−) HNSC cohort.

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Gene fusion neoantigens: Emerging targets for cancer immunotherapy

Cited by 55 publications

References 63 publications

Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1

Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1

dbPepNeo2.0: A Database for Human Tumor Neoantigen Peptides From Mass Spectrometry and TCR Recognition

The characteristics and clinical relevance of tumor fusion burden in head and neck squamous cell carcinoma

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