Proteogenomic discovery of cancer antigens: Neoantigens and beyond

Kanaseki, Takayuki; Tokita, Serina; Torigoe, Toshihiko

doi:10.1111/pin.12841

Cited by 10 publications

(6 citation statements)

References 40 publications

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“…After identifying tumor-specific mutations, several in silico peptide prediction algorithms are applied to filter the neoantigen candidates in terms of their binding capacity to MHC molecules ( (accessed on 1 December 2021)). In addition, the identification of specific neoepitopes eluted from tumor MHC molecules through immunopeptidomics, or LC-MS/MS-based immunopeptidomics, confirms that the neoepitopes are processed and presented at the cell surface [ 18 ]. In this manner, we approach the identification of actual neoantigens (defined as recognized by T cells), which are derived from only a small fraction of all identified tumor-specific mutations.…”

Section: Discussionmentioning

confidence: 99%

Identification of Neoantigens in Two Murine Gastric Cancer Cell Lines Leading to the Neoantigen-Based Immunotherapy

Nagaoka

Sun

Kobayashi

et al. 2021

Cancers

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To develop combination immunotherapies for gastric cancers, immunologically well-characterized preclinical models are crucial. Here, we leveraged two transplantable murine gastric cancer cell lines, YTN2 and YTN16, derived from the same parental line but differing in their susceptibility to immune rejection. We established their differential sensitivity to immune checkpoint inhibitors (ICI) and identified neoantigens. Although anti-CTLA-4 mAbs eradicated YTN16 tumors in 4 of 5 mice, anti-PD-1 and anti-PD-L1 mAbs failed to eradicate YTN16 tumors. Using whole-exome and RNA sequencing, we identified two and three neoantigens in YTN2 and YTN16, respectively. MHC class I ligandome analysis detected the expression of only one of these neoantigens, mutated Cdt1, but the exact length of MHC binding peptide was determined. Dendritic cell vaccine loaded with neoepitope peptides and adoptive transfer of neoantigen-specific CD8+ T cells successfully inhibited the YTN16 tumor growth. Targeting mutated Cdt1 had better efficacy for controlling the tumor. Therefore, mutated Cdt1 was the dominant neoantigen in these tumor cells. More mCdt1 peptides were bound to MHC class I and presented on YTN2 surface than YTN16. This might be one of the reasons why YTN2 was rejected while YTN16 grew in immune-competent mice.

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Section: Discussionmentioning

confidence: 99%

Identification of Neoantigens in Two Murine Gastric Cancer Cell Lines Leading to the Neoantigen-Based Immunotherapy

Nagaoka

Sun

Kobayashi

et al. 2021

Cancers

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“…Applied to HLA ligandome analysis, proteogenomics addresses two main issues—the actual presentation of HLA peptides in the genomic analysis and the need for patient- or sample-specific mutation databases in order to search for spectra data [ 149 ]. The main rationale is the use of exome sequencing mutation calling in order to identify mutations in tumor samples and RNA-seq to confirm their expression.…”

Section: In Vitro Methods For Hla Ligand Enrichmentmentioning

confidence: 99%

Uncovering the Tumor Antigen Landscape: What to Know about the Discovery Process

Feola

Chiaro

Martins

et al. 2020

Cancers

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According to the latest available data, cancer is the second leading cause of death, highlighting the need for novel cancer therapeutic approaches. In this context, immunotherapy is emerging as a reliable first-line treatment for many cancers, particularly metastatic melanoma. Indeed, cancer immunotherapy has attracted great interest following the recent clinical approval of antibodies targeting immune checkpoint molecules, such as PD-1, PD-L1, and CTLA-4, that release the brakes of the immune system, thus reviving a field otherwise poorly explored. Cancer immunotherapy mainly relies on the generation and stimulation of cytotoxic CD8 T lymphocytes (CTLs) within the tumor microenvironment (TME), priming T cells and establishing efficient and durable anti-tumor immunity. Therefore, there is a clear need to define and identify immunogenic T cell epitopes to use in therapeutic cancer vaccines. Naturally presented antigens in the human leucocyte antigen-1 (HLA-I) complex on the tumor surface are the main protagonists in evocating a specific anti-tumor CD8+ T cell response. However, the methodologies for their identification have been a major bottleneck for their reliable characterization. Consequently, the field of antigen discovery has yet to improve. The current review is intended to define what are today known as tumor antigens, with a main focus on CTL antigenic peptides. We also review the techniques developed and employed to date for antigen discovery, exploring both the direct elution of HLA-I peptides and the in silico prediction of epitopes. Finally, the last part of the review analyses the future challenges and direction of the antigen discovery field.

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“…The process of immune response to cancer cells is being studied with the goal of designing therapeutic interventions known as cancer vaccinations that attempt to elicit the T-cell immune response against cancer cells [ 275–277 ]. Proteogenomics can greatly accelerate the pace of neoantigen discovery and by providing candidate clonal neoantigens result in a more efficient vaccination process [ 278 , 279 ]. Moreover, proteogenomics studies can help delineate the underlying mechanisms of immune system evasion by cancer cells [ 280 ].…”

Section: Multilayer Approachesmentioning

confidence: 99%

Prospects and challenges of cancer systems medicine: from genes to disease networks

Karimi

Abolmaali

et al. 2021

Briefings in Bioinformatics

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It is becoming evident that holistic perspectives toward cancer are crucial in deciphering the overwhelming complexity of tumors. Single-layer analysis of genome-wide data has greatly contributed to our understanding of cellular systems and their perturbations. However, fundamental gaps in our knowledge persist and hamper the design of effective interventions. It is becoming more apparent than ever, that cancer should not only be viewed as a disease of the genome but as a disease of the cellular system. Integrative multilayer approaches are emerging as vigorous assets in our endeavors to achieve systemic views on cancer biology. Herein, we provide a comprehensive review of the approaches, methods and technologies that can serve to achieve systemic perspectives of cancer. We start with genome-wide single-layer approaches of omics analyses of cellular systems and move on to multilayer integrative approaches in which in-depth descriptions of proteogenomics and network-based data analysis are provided. Proteogenomics is a remarkable example of how the integration of multiple levels of information can reduce our blind spots and increase the accuracy and reliability of our interpretations and network-based data analysis is a major approach for data interpretation and a robust scaffold for data integration and modeling. Overall, this review aims to increase cross-field awareness of the approaches and challenges regarding the omics-based study of cancer and to facilitate the necessary shift toward holistic approaches.

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Proteogenomic discovery of cancer antigens: Neoantigens and beyond

Cited by 10 publications

References 40 publications

Identification of Neoantigens in Two Murine Gastric Cancer Cell Lines Leading to the Neoantigen-Based Immunotherapy

Identification of Neoantigens in Two Murine Gastric Cancer Cell Lines Leading to the Neoantigen-Based Immunotherapy

Uncovering the Tumor Antigen Landscape: What to Know about the Discovery Process

Prospects and challenges of cancer systems medicine: from genes to disease networks

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