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Modalities to identify clinically actionable neoantigens
Takamasa Ishino1, Yosuke Togashi1,2,3
1Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan.
Abstract:
Immune checkpoint inhibitors (ICIs), which restore antitumor immunity mediated by T cells, have caused a paradigm shift in cancer therapy. However, only a subset of patients achieve durable clinical responses, highlighting the need to better understand the mechanisms that determine antitumor immunity. Cancer-specific neoantigens are considered key determinants of effective immune responses because they are recognized as non-self by T cells and can induce strong immune responses. Accordingly, neoantigens are considered promising targets for cancer vaccines and adoptive cell therapies. Neoantigens have conventionally been considered to arise from somatic mutations and have been identified using whole-exome sequencing (WES). However, the number of neoantigens identified with WES remains limited. In contrast, advances in technology have revealed that peptides derived from various sources, including noncoding regions, are immunogenic and function as neoantigens. In particular, human leukocyte antigen (HLA) ligandome analyses, which enabled the direct identification of peptides presented on HLA molecules in combination with various sequencing technologies, have extended the landscape of neoantigen sources. However, in many cases, the immunogenicity of the identified neoantigen candidates has not been experimentally evaluated. Recently, several experimental platforms have been developed to validate neoantigen immunogenicity, which can be complemented by single-cell RNA/T-cell receptor sequencing to identify tumor-reactive T cell clones. In this review, we summarize current neoantigen identification strategies and discuss the challenges and future perspectives in neoantigen research.
Insights
Immune checkpoint inhibitors (ICIs) show promise in cancer therapy, but understanding antitumor immunity is key. Neoantigens, peptides recognized by T cells, are crucial for effective immune responses and cancer treatment strategies.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by restoring T cell-mediated antitumor immunity.
- Durable clinical responses to ICIs are limited to a subset of patients, necessitating a deeper understanding of antitumor immunity mechanisms.
- Cancer-specific neoantigens are critical for potent T cell responses and are promising targets for cancer vaccines and adoptive cell therapies.
Purpose of the Study:
- To review current strategies for identifying cancer neoantigens.
- To discuss the challenges and future directions in neoantigen research.
- To highlight the importance of neoantigen immunogenicity validation.
Main Methods:
- Conventional neoantigen identification relies on whole-exome sequencing (WES) of somatic mutations.
- Advanced techniques, including human leukocyte antigen (HLA) ligandome analysis and various sequencing technologies, expand the sources of immunogenic neoantigens beyond somatic mutations.
- Experimental platforms and single-cell RNA/T-cell receptor sequencing are employed to validate neoantigen immunogenicity and identify tumor-reactive T cell clones.
Main Results:
- Whole-exome sequencing (WES) has limitations in identifying a sufficient number of neoantigens.
- Emerging technologies reveal immunogenic peptides from diverse sources, including noncoding regions, as functional neoantigens.
- Direct identification of HLA-presented peptides via HLA ligandome analysis broadens the scope of known neoantigen sources.
Conclusions:
- Neoantigen identification has evolved beyond somatic mutations to include peptides from various genomic regions.
- Experimental validation of neoantigen immunogenicity is crucial but often lacking.
- Future research should focus on refining neoantigen identification and validation strategies to improve cancer immunotherapy efficacy.
