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Immunogenic neoantigens derived from gene fusions stimulate T cell responses
Anti-tumor immunity is driven by self vs. non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immuno...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558662/ https://www.ncbi.nlm.nih.gov/pubmed/31011208 http://dx.doi.org/10.1038/s41591-019-0434-2 |
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author | Yang, Wei Lee, Ken-Wing Srivastava, Raghvendra M. Kuo, Fengshen Krishna, Chirag Chowell, Diego Makarov, Vladimir Hoen, Douglas Dalin, Martin G. Wexler, Leonard Ghossein, Ronald Katabi, Nora Nadeem, Zaineb Cohen, Marc A. Tian, S. Ken Robine, Nicolas Arora, Kanika Geiger, Heather Agius, Phaedra Bouvier, Nancy Huberman, Kety Vanness, Katelynd Havel, Jonathan J. Sims, Jennifer S. Samstein, Robert M. Mandal, Rajarsi Tepe, Justin Ganly, Ian Ho, Alan L. Riaz, Nadeem Wong, Richard J. Shukla, Neerav Chan, Timothy A. Morris, Luc G.T. |
author_facet | Yang, Wei Lee, Ken-Wing Srivastava, Raghvendra M. Kuo, Fengshen Krishna, Chirag Chowell, Diego Makarov, Vladimir Hoen, Douglas Dalin, Martin G. Wexler, Leonard Ghossein, Ronald Katabi, Nora Nadeem, Zaineb Cohen, Marc A. Tian, S. Ken Robine, Nicolas Arora, Kanika Geiger, Heather Agius, Phaedra Bouvier, Nancy Huberman, Kety Vanness, Katelynd Havel, Jonathan J. Sims, Jennifer S. Samstein, Robert M. Mandal, Rajarsi Tepe, Justin Ganly, Ian Ho, Alan L. Riaz, Nadeem Wong, Richard J. Shukla, Neerav Chan, Timothy A. Morris, Luc G.T. |
author_sort | Yang, Wei |
collection | PubMed |
description | Anti-tumor immunity is driven by self vs. non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole genome sequencing (WGS) and RNA sequencing (RNA-seq), we identified a novel gene fusion, and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration, and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens, and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration. |
format | Online Article Text |
id | pubmed-6558662 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
record_format | MEDLINE/PubMed |
spelling | pubmed-65586622019-10-22 Immunogenic neoantigens derived from gene fusions stimulate T cell responses Yang, Wei Lee, Ken-Wing Srivastava, Raghvendra M. Kuo, Fengshen Krishna, Chirag Chowell, Diego Makarov, Vladimir Hoen, Douglas Dalin, Martin G. Wexler, Leonard Ghossein, Ronald Katabi, Nora Nadeem, Zaineb Cohen, Marc A. Tian, S. Ken Robine, Nicolas Arora, Kanika Geiger, Heather Agius, Phaedra Bouvier, Nancy Huberman, Kety Vanness, Katelynd Havel, Jonathan J. Sims, Jennifer S. Samstein, Robert M. Mandal, Rajarsi Tepe, Justin Ganly, Ian Ho, Alan L. Riaz, Nadeem Wong, Richard J. Shukla, Neerav Chan, Timothy A. Morris, Luc G.T. Nat Med Article Anti-tumor immunity is driven by self vs. non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole genome sequencing (WGS) and RNA sequencing (RNA-seq), we identified a novel gene fusion, and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration, and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens, and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration. 2019-04-22 2019-05 /pmc/articles/PMC6558662/ /pubmed/31011208 http://dx.doi.org/10.1038/s41591-019-0434-2 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Yang, Wei Lee, Ken-Wing Srivastava, Raghvendra M. Kuo, Fengshen Krishna, Chirag Chowell, Diego Makarov, Vladimir Hoen, Douglas Dalin, Martin G. Wexler, Leonard Ghossein, Ronald Katabi, Nora Nadeem, Zaineb Cohen, Marc A. Tian, S. Ken Robine, Nicolas Arora, Kanika Geiger, Heather Agius, Phaedra Bouvier, Nancy Huberman, Kety Vanness, Katelynd Havel, Jonathan J. Sims, Jennifer S. Samstein, Robert M. Mandal, Rajarsi Tepe, Justin Ganly, Ian Ho, Alan L. Riaz, Nadeem Wong, Richard J. Shukla, Neerav Chan, Timothy A. Morris, Luc G.T. Immunogenic neoantigens derived from gene fusions stimulate T cell responses |
title | Immunogenic neoantigens derived from gene fusions stimulate T cell responses |
title_full | Immunogenic neoantigens derived from gene fusions stimulate T cell responses |
title_fullStr | Immunogenic neoantigens derived from gene fusions stimulate T cell responses |
title_full_unstemmed | Immunogenic neoantigens derived from gene fusions stimulate T cell responses |
title_short | Immunogenic neoantigens derived from gene fusions stimulate T cell responses |
title_sort | immunogenic neoantigens derived from gene fusions stimulate t cell responses |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558662/ https://www.ncbi.nlm.nih.gov/pubmed/31011208 http://dx.doi.org/10.1038/s41591-019-0434-2 |
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