2. Academic Validation
  3. Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

  • Nature. 2023 Apr 12. doi: 10.1038/s41586-023-05771-9.
Kevin W Ng # 1,  Jesse Boumelha # 2,  Katey S S Enfield # 3,  Jorge Almagro 4,  Hongui Cha 5 6,  Oriol Pich 3,  Takahiro Karasaki 3 6 7,  David A Moore 3 6 8,  Roberto Salgado 9 10,  Monica Sivakumar 6,  George Young 1 11,  Miriam Molina-Arcas 2,  Sophie de Carné Trécesson 2,  Panayiotis Anastasiou 2,  Annika Fendler 12,  Lewis Au 12 13,  Scott T C Shepherd 12 13,  Carlos Martínez-Ruiz 6 14,  Clare Puttick 3 6 14,  James R M Black 6 14,  Thomas B K Watkins 3,  Hyemin Kim 5,  Seohee Shim 15,  Nikhil Faulkner 1 16,  Jan Attig 1,  Selvaraju Veeriah 6,  Neil Magno 6,  Sophia Ward 3 6 17,  Alexander M Frankell 3 6,  Maise Al Bakir 3 6,  Emilia L Lim 3 6,  Mark S Hill 3,  Gareth A Wilson 3,  Daniel E Cook 3,  Nicolai J Birkbak 3 6 18 19 20,  Axel Behrens 4 21 22 23,  Nadia Yousaf 13 24,  Sanjay Popat 24 25,  Allan Hackshaw 26,  TRACERx Consortium,  CAPTURE Consortium,  Crispin T Hiley 3 6,  Kevin Litchfield 6 27,  Nicholas McGranahan 6 14,  Mariam Jamal-Hanjani 6 7 28,  James Larkin 13 29,  Se-Hoon Lee 5 15,  Samra Turajlic 12 13 29,  Charles Swanton 30 31 32,  Julian Downward 33,  George Kassiotis 34 35
Affiliations

Affiliations

  • 1 Retroviral Immunology Laboratory, The Francis Crick Institute, London, UK.
  • 2 Oncogene Biology Laboratory, The Francis Crick Institute, London, UK.
  • 3 Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
  • 4 Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.
  • 5 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
  • 6 Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
  • 7 Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK.
  • 8 Department of Cellular Pathology, University College London Hospitals, London, UK.
  • 9 Department of Pathology, ZAS Hospitals, Antwerp, Belgium.
  • 10 Division of Research, Peter MacCallum Cancer Centre, Melbourne, Queensland, Australia.
  • 11 Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, UK.
  • 12 Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK.
  • 13 Renal and Skin Units, The Royal Marsden Hospital, London, UK.
  • 14 Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
  • 15 Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
  • 16 National Heart and Lung Institute, Imperial College London, London, UK.
  • 17 Advanced Sequencing Facility, The Francis Crick Institute, London, UK.
  • 18 Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • 19 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • 20 Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
  • 21 Cancer Stem Cell Laboratory, Institute of Cancer Research, London, UK.
  • 22 Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK.
  • 23 CRUK Convergence Science Centre, Imperial College, London, UK.
  • 24 Lung Unit, The Royal Marsden Hospital, London, UK.
  • 25 Division of Clinical Studies, The Institute of Cancer Research, London, UK.
  • 26 Cancer Research UK and University College London Cancer Trials Centre, London, UK.
  • 27 Tumour Immunogenomics and Immunosurveillance Laboratory, University College London Cancer Institute, London, UK.
  • 28 Department of Oncology, University College London Hospitals, London, UK.
  • 29 Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK.
  • 30 Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. [email protected].
  • 31 Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. [email protected].
  • 32 Department of Oncology, University College London Hospitals, London, UK. [email protected].
  • 33 Oncogene Biology Laboratory, The Francis Crick Institute, London, UK. [email protected].
  • 34 Retroviral Immunology Laboratory, The Francis Crick Institute, London, UK. [email protected].
  • 35 Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK. [email protected].
  • # Contributed equally.
PMID: 37046094 DOI: 10.1038/s41586-023-05771-9
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-130149
    99.93%, KRAS G12C Inhibitor
    Ras