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Antibodies against endogenous retroviruses promote lung cancer immunotherapy
B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)(1,2). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mec...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10115647/ https://www.ncbi.nlm.nih.gov/pubmed/37046094 http://dx.doi.org/10.1038/s41586-023-05771-9 |
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author | Ng, Kevin W. Boumelha, Jesse Enfield, Katey S. S. Almagro, Jorge Cha, Hongui Pich, Oriol Karasaki, Takahiro Moore, David A. Salgado, Roberto Sivakumar, Monica Young, George Molina-Arcas, Miriam de Carné Trécesson, Sophie Anastasiou, Panayiotis Fendler, Annika Au, Lewis Shepherd, Scott T. C. Martínez-Ruiz, Carlos Puttick, Clare Black, James R. M. Watkins, Thomas B. K. Kim, Hyemin Shim, Seohee Faulkner, Nikhil Attig, Jan Veeriah, Selvaraju Magno, Neil Ward, Sophia Frankell, Alexander M. Al Bakir, Maise Lim, Emilia L. Hill, Mark S. Wilson, Gareth A. Cook, Daniel E. Birkbak, Nicolai J. Behrens, Axel Yousaf, Nadia Popat, Sanjay Hackshaw, Allan Hiley, Crispin T. Litchfield, Kevin McGranahan, Nicholas Jamal-Hanjani, Mariam Larkin, James Lee, Se-Hoon Turajlic, Samra Swanton, Charles Downward, Julian Kassiotis, George |
author_facet | Ng, Kevin W. Boumelha, Jesse Enfield, Katey S. S. Almagro, Jorge Cha, Hongui Pich, Oriol Karasaki, Takahiro Moore, David A. Salgado, Roberto Sivakumar, Monica Young, George Molina-Arcas, Miriam de Carné Trécesson, Sophie Anastasiou, Panayiotis Fendler, Annika Au, Lewis Shepherd, Scott T. C. Martínez-Ruiz, Carlos Puttick, Clare Black, James R. M. Watkins, Thomas B. K. Kim, Hyemin Shim, Seohee Faulkner, Nikhil Attig, Jan Veeriah, Selvaraju Magno, Neil Ward, Sophia Frankell, Alexander M. Al Bakir, Maise Lim, Emilia L. Hill, Mark S. Wilson, Gareth A. Cook, Daniel E. Birkbak, Nicolai J. Behrens, Axel Yousaf, Nadia Popat, Sanjay Hackshaw, Allan Hiley, Crispin T. Litchfield, Kevin McGranahan, Nicholas Jamal-Hanjani, Mariam Larkin, James Lee, Se-Hoon Turajlic, Samra Swanton, Charles Downward, Julian Kassiotis, George |
author_sort | Ng, Kevin W. |
collection | PubMed |
description | B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)(1,2). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive(1,2). Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma(3). We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response. |
format | Online Article Text |
id | pubmed-10115647 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101156472023-04-21 Antibodies against endogenous retroviruses promote lung cancer immunotherapy Ng, Kevin W. Boumelha, Jesse Enfield, Katey S. S. Almagro, Jorge Cha, Hongui Pich, Oriol Karasaki, Takahiro Moore, David A. Salgado, Roberto Sivakumar, Monica Young, George Molina-Arcas, Miriam de Carné Trécesson, Sophie Anastasiou, Panayiotis Fendler, Annika Au, Lewis Shepherd, Scott T. C. Martínez-Ruiz, Carlos Puttick, Clare Black, James R. M. Watkins, Thomas B. K. Kim, Hyemin Shim, Seohee Faulkner, Nikhil Attig, Jan Veeriah, Selvaraju Magno, Neil Ward, Sophia Frankell, Alexander M. Al Bakir, Maise Lim, Emilia L. Hill, Mark S. Wilson, Gareth A. Cook, Daniel E. Birkbak, Nicolai J. Behrens, Axel Yousaf, Nadia Popat, Sanjay Hackshaw, Allan Hiley, Crispin T. Litchfield, Kevin McGranahan, Nicholas Jamal-Hanjani, Mariam Larkin, James Lee, Se-Hoon Turajlic, Samra Swanton, Charles Downward, Julian Kassiotis, George Nature Article B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)(1,2). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive(1,2). Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma(3). We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response. Nature Publishing Group UK 2023-04-12 2023 /pmc/articles/PMC10115647/ /pubmed/37046094 http://dx.doi.org/10.1038/s41586-023-05771-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ng, Kevin W. Boumelha, Jesse Enfield, Katey S. S. Almagro, Jorge Cha, Hongui Pich, Oriol Karasaki, Takahiro Moore, David A. Salgado, Roberto Sivakumar, Monica Young, George Molina-Arcas, Miriam de Carné Trécesson, Sophie Anastasiou, Panayiotis Fendler, Annika Au, Lewis Shepherd, Scott T. C. Martínez-Ruiz, Carlos Puttick, Clare Black, James R. M. Watkins, Thomas B. K. Kim, Hyemin Shim, Seohee Faulkner, Nikhil Attig, Jan Veeriah, Selvaraju Magno, Neil Ward, Sophia Frankell, Alexander M. Al Bakir, Maise Lim, Emilia L. Hill, Mark S. Wilson, Gareth A. Cook, Daniel E. Birkbak, Nicolai J. Behrens, Axel Yousaf, Nadia Popat, Sanjay Hackshaw, Allan Hiley, Crispin T. Litchfield, Kevin McGranahan, Nicholas Jamal-Hanjani, Mariam Larkin, James Lee, Se-Hoon Turajlic, Samra Swanton, Charles Downward, Julian Kassiotis, George Antibodies against endogenous retroviruses promote lung cancer immunotherapy |
title | Antibodies against endogenous retroviruses promote lung cancer immunotherapy |
title_full | Antibodies against endogenous retroviruses promote lung cancer immunotherapy |
title_fullStr | Antibodies against endogenous retroviruses promote lung cancer immunotherapy |
title_full_unstemmed | Antibodies against endogenous retroviruses promote lung cancer immunotherapy |
title_short | Antibodies against endogenous retroviruses promote lung cancer immunotherapy |
title_sort | antibodies against endogenous retroviruses promote lung cancer immunotherapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10115647/ https://www.ncbi.nlm.nih.gov/pubmed/37046094 http://dx.doi.org/10.1038/s41586-023-05771-9 |
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