Mutation-Derived Neoantigens for Cancer Immunotherapy
Mutation-derived neoantigens distinguish tumor from normal cells. T cells can sense the HLA-presented mutations, recognize tumor cells as non-self and destroy them. Therapeutically, immunotherapy antibodies can increase the virulence of the immune system by increasing T-cell cytotoxicity targeted to...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-08-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.01856/full |
| _version_ | 1819161685803401216 |
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| author | John C. Castle Mohamed Uduman Simarjot Pabla Robert B. Stein Jennifer S. Buell |
| author_facet | John C. Castle Mohamed Uduman Simarjot Pabla Robert B. Stein Jennifer S. Buell |
| author_sort | John C. Castle |
| collection | DOAJ |
| description | Mutation-derived neoantigens distinguish tumor from normal cells. T cells can sense the HLA-presented mutations, recognize tumor cells as non-self and destroy them. Therapeutically, immunotherapy antibodies can increase the virulence of the immune system by increasing T-cell cytotoxicity targeted toward neoantigens. Neoantigen vaccines act through antigen-presenting cells, such as dendritic cells, to activate patient-endogenous T cells that recognize vaccine-encoded mutations. Infusion of mutation-targeting T cells by adoptive cell therapy (ACT) directly increases the number and frequency of cytotoxic T cells recognizing and killing tumor cells. At the same time, publicly-funded consortia have profiled tumor genomes across many indications, identifying mutations in each tumor. For example, we find basal and HER2 positive tumors contain more mutated proteins and more TP53 mutations than luminal A/B breast tumors. HPV negative tumors have more mutated proteins than HPV positive head and neck tumors and in agreement with the hypothesis that HPV activity interferes with p53 activity, only 14% of the HPV positive mutations have TP53 mutations vs. 86% of the HPV negative tumors. Lung adenocarcinomas in smokers have over four times more mutated proteins relative to those in never smokers (median 248 vs. 61, respectively). With an eye toward immunotherapy applications, we review the spectrum of mutations in multiple indications, show variations in indication sub-types, and examine intra- and inter-indication prevalence of re-occurring mutation neoantigens that could be used for warehouse vaccines and ACT. |
| first_indexed | 2024-12-22T17:16:17Z |
| format | Article |
| id | doaj.art-586ad57d3b344640b7693de49af58947 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T17:16:17Z |
| publishDate | 2019-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-586ad57d3b344640b7693de49af589472022-12-21T18:18:57ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-08-011010.3389/fimmu.2019.01856449065Mutation-Derived Neoantigens for Cancer ImmunotherapyJohn C. CastleMohamed UdumanSimarjot PablaRobert B. SteinJennifer S. BuellMutation-derived neoantigens distinguish tumor from normal cells. T cells can sense the HLA-presented mutations, recognize tumor cells as non-self and destroy them. Therapeutically, immunotherapy antibodies can increase the virulence of the immune system by increasing T-cell cytotoxicity targeted toward neoantigens. Neoantigen vaccines act through antigen-presenting cells, such as dendritic cells, to activate patient-endogenous T cells that recognize vaccine-encoded mutations. Infusion of mutation-targeting T cells by adoptive cell therapy (ACT) directly increases the number and frequency of cytotoxic T cells recognizing and killing tumor cells. At the same time, publicly-funded consortia have profiled tumor genomes across many indications, identifying mutations in each tumor. For example, we find basal and HER2 positive tumors contain more mutated proteins and more TP53 mutations than luminal A/B breast tumors. HPV negative tumors have more mutated proteins than HPV positive head and neck tumors and in agreement with the hypothesis that HPV activity interferes with p53 activity, only 14% of the HPV positive mutations have TP53 mutations vs. 86% of the HPV negative tumors. Lung adenocarcinomas in smokers have over four times more mutated proteins relative to those in never smokers (median 248 vs. 61, respectively). With an eye toward immunotherapy applications, we review the spectrum of mutations in multiple indications, show variations in indication sub-types, and examine intra- and inter-indication prevalence of re-occurring mutation neoantigens that could be used for warehouse vaccines and ACT.https://www.frontiersin.org/article/10.3389/fimmu.2019.01856/fullcancermutationsneoantigensimmunotherapytherapeutic vaccineTCR |
| spellingShingle | John C. Castle Mohamed Uduman Simarjot Pabla Robert B. Stein Jennifer S. Buell Mutation-Derived Neoantigens for Cancer Immunotherapy Frontiers in Immunology cancer mutations neoantigens immunotherapy therapeutic vaccine TCR |
| title | Mutation-Derived Neoantigens for Cancer Immunotherapy |
| title_full | Mutation-Derived Neoantigens for Cancer Immunotherapy |
| title_fullStr | Mutation-Derived Neoantigens for Cancer Immunotherapy |
| title_full_unstemmed | Mutation-Derived Neoantigens for Cancer Immunotherapy |
| title_short | Mutation-Derived Neoantigens for Cancer Immunotherapy |
| title_sort | mutation derived neoantigens for cancer immunotherapy |
| topic | cancer mutations neoantigens immunotherapy therapeutic vaccine TCR |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.01856/full |
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