Antibodies against endogenous retroviruses promote lung cancer immunotherapy.
Creators: name: Ng, Kevin W
name: Boumelha, Jesse
name: Enfield, Katey SS
name: Almagro, Jorge
name: Cha, Hongui
name: Pich, Oriol
name: Karasaki, Takahiro
name: Moore, David A
name: Salgado, Roberto
name: Sivakumar, Monica
name: Young, George
name: Molina-Arcas, Miriam
name: de Carné Trécesson, Sophie
name: Anastasiou, Panayiotis
name: Fendler, Annika
name: Au, Lewis
name: Shepherd, Scott TC
name: Martínez-Ruiz, Carlos
name: Puttick, Clare
name: Black, James RM
name: Watkins, Thomas BK
name: Kim, Hyemin
name: Shim, Seohee
name: Faulkner, Nikhil
name: Attig, Jan
name: Veeriah, Selvaraju
name: Magno, Neil
name: Ward, Sophia
name: Frankell, Alexander M
name: Al Bakir, Maise
name: Lim, Emilia L
name: Hill, Mark S
name: Wilson, Gareth A
name: Cook, Daniel E
name: Birkbak, Nicolai J
name: Behrens, Axel
name: Yousaf, Nadia
name: Popat, Sanjay
name: Hackshaw, Allan
name: Consortium, TRACERx
name: Consortium, CAPTURE
name: Hiley, Crispin T
name: Litchfield, Kevin
name: McGranahan, Nicholas
name: Jamal-Hanjani, Mariam
name: Larkin, James
name: Lee, Se-Hoon
name: Turajlic, Samra
name: Swanton, Charles
name: Downward, Julian
name: Kassiotis, George
Publisher: name: The Francis Crick Institute
Year: 2023
Subjects: subject: Model organisms
subject: Tumour Biology
subject: Signalling &amp; Oncogenes
subject: Gene Expression
subject: Genetics &amp; Genomics
subject: Genome Integrity &amp; Repair
subject: Human Biology &amp; Physiology
subject: Cell Biology
subject: Cell Cycle &amp; Chromosomes
subject: Stem Cells
subject: Chemical Biology &amp; High Throughput
subject: Infectious Disease
subject: Ecology,Evolution &amp; Ethology
subject: Immunology
subject: FOS: Clinical medicine
subject: Computational &amp; Systems Biology

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 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.