MHC II immunogenicity shapes the neoepitope landscape in human tumors
Despite advances in predicting physical peptide-major histocompatibility complex I (pMHC I) binding, it remains challenging to identify functionally immunogenic neoepitopes, especially for MHC II. By using the results of >36,000 immunogenicity assay, we developed a method to identify pMHC whose s...
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| Veröffentlicht in: | Nature genetics 2023-02, Vol.55 (2), p.221-231 |
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| creator | Kim, Jeong Yeon Cha, Hongui Kim, Kyeonghui Sung, Changhwan An, Jinhyeon Bang, Hyoeun Kim, Hyungjoo Yang, Jin Ok Chang, Suhwan Shin, Incheol Noh, Seung-Jae Shin, Inkyung Cho, Dae-Yeon Lee, Se-Hoon Choi, Jung Kyoon |
| description | Despite advances in predicting physical peptide-major histocompatibility complex I (pMHC I) binding, it remains challenging to identify functionally immunogenic neoepitopes, especially for MHC II. By using the results of >36,000 immunogenicity assay, we developed a method to identify pMHC whose structural alignment facilitates T cell reaction. Our method predicted neoepitopes for MHC II and MHC I that were responsive to checkpoint blockade when applied to >1,200 samples of various tumor types. To investigate selection by spontaneous immunity at the single epitope level, we analyzed the frequency spectrum of >25 million mutations in >9,000 treatment-naive tumors with >100 immune phenotypes. MHC II immunogenicity specifically lowered variant frequencies in tumors under high immune pressure, particularly with high TCR clonality and MHC II expression. A similar trend was shown for MHC I neoepitopes, but only in particular tissue types. In summary, we report immune selection imposed by MHC II-restricted natural or therapeutic T cell reactivity.
DeepNeo identifies major histocompatibility complex (MHC) I or MHC II neoepitopes that are immunogenically compatible with the T cell repertoire. It can predict neoepitopes most likely to be depleted through spontaneous immunity or through immune checkpoint blockade from untreated and immunotherapy-treated tumor datasets. |
| doi_str_mv | 10.1038/s41588-022-01273-y |
| format | Article |
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DeepNeo identifies major histocompatibility complex (MHC) I or MHC II neoepitopes that are immunogenically compatible with the T cell repertoire. It can predict neoepitopes most likely to be depleted through spontaneous immunity or through immune checkpoint blockade from untreated and immunotherapy-treated tumor datasets.</description><subject>631/114/2785</subject><subject>631/208/212</subject><subject>631/208/248</subject><subject>631/67/580</subject><subject>Agriculture</subject><subject>Amino acids</subject><subject>Animal Genetics and Genomics</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Epitopes</subject><subject>Epitopes - genetics</subject><subject>Frequency analysis</subject><subject>Frequency spectrum</subject><subject>Gene Function</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Identification methods</subject><subject>Immune checkpoint inhibitors</subject><subject>Immunogenicity</subject><subject>Immunotherapy</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Major histocompatibility complex</subject><subject>Methods</subject><subject>Mutation</subject><subject>Neoplasms - 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By using the results of >36,000 immunogenicity assay, we developed a method to identify pMHC whose structural alignment facilitates T cell reaction. Our method predicted neoepitopes for MHC II and MHC I that were responsive to checkpoint blockade when applied to >1,200 samples of various tumor types. To investigate selection by spontaneous immunity at the single epitope level, we analyzed the frequency spectrum of >25 million mutations in >9,000 treatment-naive tumors with >100 immune phenotypes. MHC II immunogenicity specifically lowered variant frequencies in tumors under high immune pressure, particularly with high TCR clonality and MHC II expression. A similar trend was shown for MHC I neoepitopes, but only in particular tissue types. In summary, we report immune selection imposed by MHC II-restricted natural or therapeutic T cell reactivity.
DeepNeo identifies major histocompatibility complex (MHC) I or MHC II neoepitopes that are immunogenically compatible with the T cell repertoire. It can predict neoepitopes most likely to be depleted through spontaneous immunity or through immune checkpoint blockade from untreated and immunotherapy-treated tumor datasets.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>36624345</pmid><doi>10.1038/s41588-022-01273-y</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-1313-8124</orcidid><orcidid>https://orcid.org/0000-0002-9219-3350</orcidid><orcidid>https://orcid.org/0000-0003-2077-8947</orcidid></addata></record> |
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| subjects | 631/114/2785 631/208/212 631/208/248 631/67/580 Agriculture Amino acids Animal Genetics and Genomics Biomedical and Life Sciences Biomedicine Cancer Cancer Research Epitopes Epitopes - genetics Frequency analysis Frequency spectrum Gene Function Human Genetics Humans Identification methods Immune checkpoint inhibitors Immunogenicity Immunotherapy Lymphocytes Lymphocytes T Major histocompatibility complex Methods Mutation Neoplasms - genetics Neoplasms - therapy Peptides Peptides - chemistry Peptides - metabolism Phenotypes Power Proteins Survival analysis T cell receptors T-Lymphocytes Tumors |
| title | MHC II immunogenicity shapes the neoepitope landscape in human tumors |
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