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Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors

Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, though in microsatellite stable tumors this association is weak and of limited clinical utility. Here, we uniformly analyzed whole exome sequencing (WES) of 249 tumors and matched normal tissue f...

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Autores principales: Miao, Diana, Margolis, Claire A., Vokes, Natalie I., Liu, David, Taylor-Weiner, Amaro, Wankowicz, Stephanie M., Adeegbe, Dennis, Keliher, Daniel, Schilling, Bastian, Tracy, Adam, Manos, Michael, Chau, Nicole G., Hanna, Glenn J., Polak, Paz, Rodig, Scott J., Signoretti, Sabina, Sholl, Lynette M., Engelman, Jeffrey A., Getz, Gad, Jänne, Pasi A., Haddad, Robert I., Choueiri, Toni K., Barbie, David A., Haq, Rizwan, Awad, Mark M., Schadendorf, Dirk, Hodi, F. Stephen, Bellmunt, Joaquim, Wong, Kwok-Kin, Hammerman, Peter, Van Allen, Eliezer M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119118/
https://www.ncbi.nlm.nih.gov/pubmed/30150660
http://dx.doi.org/10.1038/s41588-018-0200-2
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author Miao, Diana
Margolis, Claire A.
Vokes, Natalie I.
Liu, David
Taylor-Weiner, Amaro
Wankowicz, Stephanie M.
Adeegbe, Dennis
Keliher, Daniel
Schilling, Bastian
Tracy, Adam
Manos, Michael
Chau, Nicole G.
Hanna, Glenn J.
Polak, Paz
Rodig, Scott J.
Signoretti, Sabina
Sholl, Lynette M.
Engelman, Jeffrey A.
Getz, Gad
Jänne, Pasi A.
Haddad, Robert I.
Choueiri, Toni K.
Barbie, David A.
Haq, Rizwan
Awad, Mark M.
Schadendorf, Dirk
Hodi, F. Stephen
Bellmunt, Joaquim
Wong, Kwok-Kin
Hammerman, Peter
Van Allen, Eliezer M.
author_facet Miao, Diana
Margolis, Claire A.
Vokes, Natalie I.
Liu, David
Taylor-Weiner, Amaro
Wankowicz, Stephanie M.
Adeegbe, Dennis
Keliher, Daniel
Schilling, Bastian
Tracy, Adam
Manos, Michael
Chau, Nicole G.
Hanna, Glenn J.
Polak, Paz
Rodig, Scott J.
Signoretti, Sabina
Sholl, Lynette M.
Engelman, Jeffrey A.
Getz, Gad
Jänne, Pasi A.
Haddad, Robert I.
Choueiri, Toni K.
Barbie, David A.
Haq, Rizwan
Awad, Mark M.
Schadendorf, Dirk
Hodi, F. Stephen
Bellmunt, Joaquim
Wong, Kwok-Kin
Hammerman, Peter
Van Allen, Eliezer M.
author_sort Miao, Diana
collection PubMed
description Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, though in microsatellite stable tumors this association is weak and of limited clinical utility. Here, we uniformly analyzed whole exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often inter-related, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance our ability to discover clinically meaningful predictive features of response to immune checkpoint blockade.
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spelling pubmed-61191182019-02-27 Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors Miao, Diana Margolis, Claire A. Vokes, Natalie I. Liu, David Taylor-Weiner, Amaro Wankowicz, Stephanie M. Adeegbe, Dennis Keliher, Daniel Schilling, Bastian Tracy, Adam Manos, Michael Chau, Nicole G. Hanna, Glenn J. Polak, Paz Rodig, Scott J. Signoretti, Sabina Sholl, Lynette M. Engelman, Jeffrey A. Getz, Gad Jänne, Pasi A. Haddad, Robert I. Choueiri, Toni K. Barbie, David A. Haq, Rizwan Awad, Mark M. Schadendorf, Dirk Hodi, F. Stephen Bellmunt, Joaquim Wong, Kwok-Kin Hammerman, Peter Van Allen, Eliezer M. Nat Genet Article Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, though in microsatellite stable tumors this association is weak and of limited clinical utility. Here, we uniformly analyzed whole exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often inter-related, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance our ability to discover clinically meaningful predictive features of response to immune checkpoint blockade. 2018-08-27 2018-09 /pmc/articles/PMC6119118/ /pubmed/30150660 http://dx.doi.org/10.1038/s41588-018-0200-2 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
Miao, Diana
Margolis, Claire A.
Vokes, Natalie I.
Liu, David
Taylor-Weiner, Amaro
Wankowicz, Stephanie M.
Adeegbe, Dennis
Keliher, Daniel
Schilling, Bastian
Tracy, Adam
Manos, Michael
Chau, Nicole G.
Hanna, Glenn J.
Polak, Paz
Rodig, Scott J.
Signoretti, Sabina
Sholl, Lynette M.
Engelman, Jeffrey A.
Getz, Gad
Jänne, Pasi A.
Haddad, Robert I.
Choueiri, Toni K.
Barbie, David A.
Haq, Rizwan
Awad, Mark M.
Schadendorf, Dirk
Hodi, F. Stephen
Bellmunt, Joaquim
Wong, Kwok-Kin
Hammerman, Peter
Van Allen, Eliezer M.
Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors
title Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors
title_full Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors
title_fullStr Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors
title_full_unstemmed Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors
title_short Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors
title_sort genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119118/
https://www.ncbi.nlm.nih.gov/pubmed/30150660
http://dx.doi.org/10.1038/s41588-018-0200-2
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