Antibodies against endogenous retroviruses promote lung cancer immunotherapy
More about Open Access at the CrickAuthors list
Kevin Ng Jesse Boumelha Katey Enfield Jorge Almagro Hongui Cha Oriol Pich Takahiro Karasaki David A Moore Roberto Salgado Monica Sivakumar George Young Miriam Molina Arcas Sophie de Carne Panos Anastasiou Annika Fendler Lewis Au Scott Shepherd Carlos Martínez-Ruiz Clare Puttick James RM Black Tom Watkins Hyemin Kim Seohee Shim Nikhil Faulkner Jan Attig Selvaraju Veeriah Neil Magno Sophie Ward Alexander Frankell Maise Al Bakir Emilia Lim Mark S Hill Gareth Wilson Daniel E Cook Nicolai Birkbak Axel Behrens Nadia Yousaf Sanjay Popat Allan Hackshaw TRACERx Consortium CAPTURE Consortium Crispin Hiley Kevin Litchfield Nicholas McGranahan Mariam Jamal-Hanjani James Larkin Se-Hoon Lee Samra Turajlic Charles Swanton Julian Downward George Kassiotis Toggle all authors (51)
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.
Journal details
Journal Nature
Volume 616
Issue number 7957
Pages 563-573
Available online
Publication date
Full text links
Publisher website (DOI) 10.1038/s41586-023-05771-9
Europe PubMed Central 37046094
Pubmed 37046094
Keywords
Related topics
Type of publication