Antibodies against endogenous retroviruses promote lung cancer immunotherapy
Authors: Ng Kevin W. , Boumelha Jesse , Enfield Katey S. S. , Almagro Jorge , Cha Hongui , Pich Oriol , Karasaki Takahiro , Moore David A. , Salgado Roberto , Sivakumar Monica , Young George , Molina-Arcas Miriam , de Carné Trécesson Sophie , Anastasiou Panayiotis , Fendler Annika , Au Lewis , Shepherd Scott T. C. , Martínez-Ruiz Carlos , Puttick Clare , Black James R. M. , Watkins Thomas B. K. , Kim Hyemin , Shim Seohee , Faulkner Nikhil , Attig Jan , Veeriah Selvaraju , Magno Neil , Ward Sophia , Frankell Alexander M. , Al Bakir Maise , Lim Emilia L. , Hill Mark S. , Wilson Gareth A. , Cook Daniel E. , Birkbak Nicolai J. , Behrens Axel , Yousaf Nadia , Popat Sanjay , Hackshaw Allan ,   TRACERx Consortium, Rowan Andrew , Huebner Ariana , Campbell Brittany B. , Bailey Chris , Lee Claudia , Biswas Dhruva , Colliver Emma , Athanasopoulou Foteini , Zhai Haoran , Rane Jayant K. , Grigoriadis Kristiana , Dietzen Michelle , Leung Michelle , Angelova Mihaela , Lucas Olivia , Al-Sawaf Othman , Rosenthal Rachel , Nicod Jerome , Bunkum Abigail , Toncheva Antonia , Abbosh Christopher , Richard Corentin , Naceur-Lombardelli Cristina , Gimeno-Valiente Francisco , Lam Jie Min , Thol Kerstin , Thakkar Krupa , Werner Sunderland Mariana , Forster Martin D. , Kanu Nnennaya , Prymas Paulina , Bentham Robert , Saghafinia Sadegh , Quezada Sergio A. , Vanloo Sharon , Zaccaria Simone , Lee Siow Ming , Hessey Sonya , Liu Wing Kin , Papadatos-Pastos Dionysis , Wilson James , Benafif Sarah , Ahmad Tanya , Borg Elaine , Falzon Mary , Khiroya Reena , Marafioti Teresa , Sharp Abigail , Pilotti Camilla , Dhanda Harjot Kaur , Chan Kitty , Gower Nicole , Leslie Rachel , Smith Sean , Nicholson Andrew G. , Lim Eric , Herrero Javier , Castignani Carla , Larose Cadieux Elizabeth , Demeulemeester Jonas , Van Loo Peter , Peggs Karl S. , Veiga Catarina , Royle Gary , Collins-Fekete Charles-Antoine , Procter Alexander James , Nair Arjun , Ahmed Asia , Taylor Magali N. , Navani Neal , Thakrar Ricky M. , Lawrence David , Patrini Davide , Nye Emma , Stone Richard Kevin , Chuter David , MacKenzie Mairead , Fraioli Francesco , Ashford Paul , Janes Sam M. , Tanić Miljana , Beck Stephan , Rice Alexandra , Devaraj Anand , Proli Chiara , Kaniu Daniel , Bhayani Harshil , Chavan Hema , Raubenheimer Hilgardt , Ambrose Lyn , Malima Mpho , Fernandes Nadia , De Sousa Paulo , Shah Pratibha , Booth Sarah , Buderi Silviu I. , Jordan Simon , Begum Sofina , Boleti Ekaterini , Stewart Aengus , Magness Alastair , Weeden Clare E. , Levi Dina , Grönroos Eva , Goldman Jacki , Escudero Mickael , Hobson Philip , Vendramin Roberto , Boeing Stefan , Denner Tamara , Barbè Vittorio , Lu Wei-Ting , Hill William , Naito Yutaka , Ramsden Zoe , Grapa Anca , Zhang Hanyun , AbdulJabbar Khalid , Pan Xiaoxi , Gilbert Kayleigh , Karamani Angeliki , Chain Benny , Pearce David R. , Karagianni Despoina , Hoxha Elena , Gálvez-Cancino Felip , Stavrou Georgia , Mastrokalos Gerasimos , Lowe Helen L. , Matos Ignacio , Reading James L. , Hartley John A. , Selvaraju Kayalvizhi , Chen Kezhong , Ensell Leah , Shah Mansi , Vasquez Marcos , Litovchenko Maria , Chervova Olga , Pawlik Piotr , Hynds Robert E. , López Saioa , Gamble Samuel , Ung Seng Kuong Anakin , Bola Supreet Kaur , Mourikis Thanos P. , Spanswick Victoria , Wu Yin , Martinoni Hoogenboom Emilie , Monk Fleur , Holding James W. , Choudhary Junaid , Bhakhri Kunal , Scarci Marco , Hayward Martin , Panagiotopoulos Nikolaos , Gorman Pat , Stephens Robert C. M. , Bandula Steve , Wong Yien Ning Sophia , Clark Tristan , Cheyne Heather , Khalil Mohammed , Richardson Shirley , Cruickshank Tracey , Naidu Babu , Matharu Gurdeep , Shaw Jacqui A. , Riley Joan , Primrose Lindsay , Le Quesne John , Blyth Kevin G. , Kerr Alastair , Clipson Alexandra , Chaturvedi Anshuman , Dive Caroline , Rothwell Dominic G. , Kilgour Elaine , Tugwood Jonathan , Priest Lynsey , Oliveira Pedro , Crosbie Philip , Price Gillian , Cave Judith , Kerr Keith M. , Lindsay Colin R. , Blackhall Fiona H. , Krebs Matthew G. , Summers Yvonne , Kirk Alan , Thomas Mathew , Asif Mo , Kostoulas Nikos , Bilancia Rocco , Middleton Gary , Shackcloth Michael J. , Leek Angela , Hodgkinson Jack Davies , Totten Nicola , Dick Craig , Robinson Lily , Russell Peter , Hewish Madeleine , Danson Sarah , Lester Jason F. , Gomes Fabio , Brown Kate , Carter Mathew , Patel Akshay J. , Osman Aya , Lacson Christer , Langman Gerald , Shackleford Helen , Djearaman Madava , Kadiri Salma , Alzetani Aiman , Richards Jennifer , Scarlett Lydia , Ingram Papawadee , Chee Serena , Austin Silvia , Bajaj Amrita , Nakas Apostolos , Sodha-Ramdeen Azmina , Fennell Dean A. , Ang Keng , Tufail Mohamad , Chowdhry Mohammed Fiyaz , Scotland Molly , Boyles Rebecca , Rathinam Sridhar , Wilson Claire , Marrone Domenic , Dulloo Sean , Montero Angeles , Smith Elaine , Fontaine Eustace , Granato Felice , Doran Helen , Novasio Juliette , Rammohan Kendadai , Joseph Leena , Bishop Paul , Shah Rajesh , Moss Stuart , Joshi Vijay , Aerts Hugo J. W. L. , Kaufmann Tom L. , Schwarz Roland F. , Kisistok Judit , Sokac Mateo , Diossy Miklos , Szallasi Zoltan , Dijkstra Krijn , Yuan Yinyin ,   CAPTURE Consortium, Byrne Fiona , Boos Laura Amanda , Shum Benjamin , Gerard Camille L. , Schmitt Andreas M. , Messiou Christina , Cunningham David , Chau Ian , Starling Naureen , Turner Nicholas , Welsh Liam , Jones Robin L. , Droney Joanne , Banerjee Susana , Tatham Kate C. , Jhanji Shaman , Harrington Kevin , Okines Alicia , Reid Alison , Young Kate , Furness Andrew J. S. , Pickering Lisa , Nicholson Emma , Kumar Sacheen , Wilkinson Katalin A. , Swerdlow Anthony , Wilkinson Robert J. , Hiley Crispin T. , Litchfield Kevin , McGranahan Nicholas , Jamal-Hanjani Mariam , Larkin James , Lee Se-Hoon , Turajlic Samra , Swanton Charles , Downward Julian , Kassiotis George 
Published: April 2023

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.