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Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer

PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs ha...

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Autores principales: Khan, Zia, Di Nucci, Flavia, Kwan, Antonia, Hammer, Christian, Mariathasan, Sanjeev, Rouilly, Vincent, Carroll, Jonathan, Fontes, Magnus, Ley Acosta, Sergio, Guardino, Ellie, Chen-Harris, Haiyin, Bhangale, Tushar, Mellman, Ira, Rosenberg, Jonathan, Powles, Thomas, Hunkapiller, Julie, Chandler, G. Scott, Albert, Matthew L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275757/
https://www.ncbi.nlm.nih.gov/pubmed/32430334
http://dx.doi.org/10.1073/pnas.1922867117
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author Khan, Zia
Di Nucci, Flavia
Kwan, Antonia
Hammer, Christian
Mariathasan, Sanjeev
Rouilly, Vincent
Carroll, Jonathan
Fontes, Magnus
Ley Acosta, Sergio
Guardino, Ellie
Chen-Harris, Haiyin
Bhangale, Tushar
Mellman, Ira
Rosenberg, Jonathan
Powles, Thomas
Hunkapiller, Julie
Chandler, G. Scott
Albert, Matthew L.
author_facet Khan, Zia
Di Nucci, Flavia
Kwan, Antonia
Hammer, Christian
Mariathasan, Sanjeev
Rouilly, Vincent
Carroll, Jonathan
Fontes, Magnus
Ley Acosta, Sergio
Guardino, Ellie
Chen-Harris, Haiyin
Bhangale, Tushar
Mellman, Ira
Rosenberg, Jonathan
Powles, Thomas
Hunkapiller, Julie
Chandler, G. Scott
Albert, Matthew L.
author_sort Khan, Zia
collection PubMed
description PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti–PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole-genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti–PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti–PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti–PD-L1 monotherapy in bladder cancer.
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spelling pubmed-72757572020-06-11 Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer Khan, Zia Di Nucci, Flavia Kwan, Antonia Hammer, Christian Mariathasan, Sanjeev Rouilly, Vincent Carroll, Jonathan Fontes, Magnus Ley Acosta, Sergio Guardino, Ellie Chen-Harris, Haiyin Bhangale, Tushar Mellman, Ira Rosenberg, Jonathan Powles, Thomas Hunkapiller, Julie Chandler, G. Scott Albert, Matthew L. Proc Natl Acad Sci U S A Biological Sciences PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti–PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole-genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti–PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti–PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti–PD-L1 monotherapy in bladder cancer. National Academy of Sciences 2020-06-02 2020-05-19 /pmc/articles/PMC7275757/ /pubmed/32430334 http://dx.doi.org/10.1073/pnas.1922867117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Khan, Zia
Di Nucci, Flavia
Kwan, Antonia
Hammer, Christian
Mariathasan, Sanjeev
Rouilly, Vincent
Carroll, Jonathan
Fontes, Magnus
Ley Acosta, Sergio
Guardino, Ellie
Chen-Harris, Haiyin
Bhangale, Tushar
Mellman, Ira
Rosenberg, Jonathan
Powles, Thomas
Hunkapiller, Julie
Chandler, G. Scott
Albert, Matthew L.
Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer
title Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer
title_full Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer
title_fullStr Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer
title_full_unstemmed Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer
title_short Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer
title_sort polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275757/
https://www.ncbi.nlm.nih.gov/pubmed/32430334
http://dx.doi.org/10.1073/pnas.1922867117
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