Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Kevin W. Ng, Jesse Boumelha, Katey S. S. Enfield, Jorge Almagro, Hongui Cha, Oriol Pich, Takahiro Karasaki, David A. Moore, Roberto Salgado, Monica Sivakumar, George Young, Miriam Molina-Arcas, Sophie Carné Trécesson, Panayiotis Anastasiou, Annika Fendler, Lewis Au, Scott T. C. Shepherd, Carlos Martínez-Ruiz, Clare Puttick, James R. M. Black, Thomas B. K. Watkins, Hyemin Kim, Seohee Shim, Nikhil Faulkner, Jan Attig, Selvaraju Veeriah, Neil Magno, Sophia Ward, Alexander M. Frankell, Maise Al Bakir, Emilia L. Lim, Mark S. Hill, Gareth A. Wilson, Daniel E. Cook, Nicolai J. Birkbak, Axel Behrens, Nadia Yousaf, Sanjay Popat, Allan Hackshaw, Crispin T. Hiley, Kevin Litchfield, Nicholas McGranahan, Mariam Jamal-Hanjani, James Larkin, Se-Hoon Lee, Samra Turajlic, Charles Swanton (), Julian Downward () and George Kassiotis ()
Additional contact information
Kevin W. Ng: The Francis Crick Institute
Jesse Boumelha: The Francis Crick Institute
Katey S. S. Enfield: The Francis Crick Institute
Jorge Almagro: The Francis Crick Institute
Hongui Cha: Sungkyunkwan University School of Medicine
Oriol Pich: The Francis Crick Institute
Takahiro Karasaki: The Francis Crick Institute
David A. Moore: The Francis Crick Institute
Roberto Salgado: ZAS Hospitals
Monica Sivakumar: University College London Cancer Institute
George Young: The Francis Crick Institute
Miriam Molina-Arcas: The Francis Crick Institute
Sophie Carné Trécesson: The Francis Crick Institute
Panayiotis Anastasiou: The Francis Crick Institute
Annika Fendler: The Francis Crick Institute
Lewis Au: The Francis Crick Institute
Scott T. C. Shepherd: The Francis Crick Institute
Carlos Martínez-Ruiz: University College London Cancer Institute
Clare Puttick: The Francis Crick Institute
James R. M. Black: University College London Cancer Institute
Thomas B. K. Watkins: The Francis Crick Institute
Hyemin Kim: Sungkyunkwan University School of Medicine
Seohee Shim: Sungkyunkwan University
Nikhil Faulkner: The Francis Crick Institute
Jan Attig: The Francis Crick Institute
Selvaraju Veeriah: University College London Cancer Institute
Neil Magno: University College London Cancer Institute
Sophia Ward: The Francis Crick Institute
Alexander M. Frankell: The Francis Crick Institute
Maise Al Bakir: The Francis Crick Institute
Emilia L. Lim: The Francis Crick Institute
Mark S. Hill: The Francis Crick Institute
Gareth A. Wilson: The Francis Crick Institute
Daniel E. Cook: The Francis Crick Institute
Nicolai J. Birkbak: The Francis Crick Institute
Axel Behrens: The Francis Crick Institute
Nadia Yousaf: The Royal Marsden Hospital
Sanjay Popat: The Royal Marsden Hospital
Allan Hackshaw: Cancer Research UK and University College London Cancer Trials Centre
Crispin T. Hiley: The Francis Crick Institute
Kevin Litchfield: University College London Cancer Institute
Nicholas McGranahan: University College London Cancer Institute
Mariam Jamal-Hanjani: University College London Cancer Institute
James Larkin: The Royal Marsden Hospital
Se-Hoon Lee: Sungkyunkwan University School of Medicine
Samra Turajlic: The Francis Crick Institute
Charles Swanton: The Francis Crick Institute
Julian Downward: The Francis Crick Institute
George Kassiotis: The Francis Crick Institute

Nature, 2023, vol. 616, issue 7957, 563-573

Abstract: Abstract 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 elusive1,2. 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 adenocarcinoma3. 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.

Date: 2023
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DOI: 10.1038/s41586-023-05771-9

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