RETRACTED ARTICLE: Antibodies against endogenous retroviruses promote lung cancer immunotherapy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 R. Young, Míriam Molina‐Arcas, Sophie de Carné Trécesson, Panayiotis Anastasiou, Annika Fendler, Lewis Au, Scott T.C. Shepherd, Carlos Martínez‐Ruiz, Clare Puttick, James R. Black, Thomas B.K. Watkins, Hye Min 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, Andrew Rowan, Ariana Huebner, Brittany Campbell, Chris Bailey, Claudia Lee, Dhruva Biswas, Emma Colliver, Foteini Athanasopoulou, Hao-Ran Zhai, Jayant K. Rane, Kristiana Grigoriadis, Michelle Dietzen, Michelle Leung, Mihaela Angelova, Olivia Lucas, Othman Al‐Sawaf, Rachel Rosenthal, Jérôme Nicod, Abigail Bunkum, Antonia Toncheva, Christopher Abbosh, Corentin Richard, Cristina Naceur‐Lombardelli, Francisco Gimeno-Valiente, Jie Min Lam, Kerstin Thol, Krupa Thakkar, Mariana Werner Sunderland, Martin Förster, Nnennaya Kanu, Paulina Prymas, Robert B. Bentham, Sadegh Saghafinia, Sergio A. Quezada, Sharon Vanloo, Simone Zaccaria, Siow Ming Lee, Sonya Hessey, Wing Kin Liu, Dionysis Papadatos-Pastos, James M. Wilson, Sarah Benafif, Tanya Ahmad, Elaine Borg, Mary Falzon, Reena Khiroya, Teresa Marafioti, Abigail Sharp, Camilla Pilotti, Harjot Kaur Dhanda, Kitty S. Chan, Nicole Gower, Rachel Leslie, Sean Smith, Andrew G. Nicholson, Eric Lim, Javier Herrero, Carla Castignani, Elizabeth Larose Cadieux, Jonas Demeulemeester, Peter Van Loo
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 elusive 1,2 . 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 adenocarcinoma 3 . 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.