The Francis Crick Institute
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Antibodies against endogenous retroviruses promote lung cancer immunotherapy.

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journal contribution
posted on 2023-04-20, 13:33 authored by Kevin W Ng, Jesse Boumelha, Katey SS Enfield, Jorge Almagro, Hongui Cha, Oriol Pich, Takahiro Karasaki, David A Moore, Roberto Salgado, Monica Sivakumar, George Young, Miriam Molina-Arcas, Sophie de Carné Trécesson, Panayiotis Anastasiou, Annika Fendler, Lewis Au, Scott TC Shepherd, Carlos Martínez-Ruiz, Clare Puttick, James RM Black, Thomas BK 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, TRACERx Consortium, CAPTURE Consortium, Crispin T Hiley, Kevin Litchfield, Nicholas McGranahan, Mariam Jamal-Hanjani, James Larkin, Se-Hoon Lee, Samra Turajlic, Charles Swanton, Julian Downward, George Kassiotis
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.


Crick (Grant ID: CC2112, Grant title: Wilkinson CC2112) Crick (Grant ID: CC2008, Grant title: Van Loo CC2008) Crick (Grant ID: CC2044, Grant title: Turajlic CC2044) Crick (Grant ID: CC2041, Grant title: Swanton CC2041) Crick (Grant ID: CC2088, Grant title: Kassiotis CC2088) Crick (Grant ID: CC2097, Grant title: Downward CC2097) Crick (Grant ID: CC2015, Grant title: Behrens CC2015) Novo Nordisk UK Research Foundation (Grant ID: NNF15OC0016584, Grant title: NovoNordisk Foundation 16584) Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics) Crick (Grant ID: CC1064, Grant title: STP Advanced Sequencing) Crick (Grant ID: CC1061, Grant title: STP Experimental Histopathology) Crick (Grant ID: CC1062, Grant title: STP Flow Cytometry) Crick (Grant ID: CC1119, Grant title: STP Scientific Computing)