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Antibodies against endogenous retroviruses promote lung cancer immunotherapy

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Item Type:Article
Title:Antibodies against endogenous retroviruses promote lung cancer immunotherapy
Creators Name:Ng, K.W. and Boumelha, J. and Enfield, K.S.S. and Almagro, J. and Cha, H. and Pich, O. and Karasaki, T. and Moore, D.A. and Salgado, R. and Sivakumar, M. and Young, G. and Molina-Arcas, M. and de Carné Trécesson, S. and Anastasiou, P. and Fendler, A. and Au, L. and Shepherd, S.T.C. and Martínez-Ruiz, C. and Puttick, C. and Black, J.R.M. and Watkins, T.B.K. and Kim, H. and Shim, S. and Faulkner, N. and Attig, J. and Veeriah, S. and Magno, N. and Ward, S. and Frankell, A.M. and Al Bakir, M. and Lim, E.L. and Hill, M.S. and Wilson, G.A. and Cook, D.E. and Birkbak, N.J. and Behrens, A. and Yousaf, N. and Popat, S. and Hackshaw, A. and Hiley, C.T. and Litchfield, K. and McGranahan, N. and Jamal-Hanjani, M. and Larkin, J. and Lee, S.H. and Turajlic, S. and Swanton, C. and Downward, J. and Kassiotis, G.
Abstract:B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). 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(. 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. 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.
Keywords:Cancer Genomics, Non-Small-Cell Lung Cancer, Tumour Immunology, Animals, Mice
Publisher:Nature Publishing Group
Page Range:563-573
Date:20 April 2023
Additional Information:Tom Kaufmann is a member of TRACERx Consortium
Official Publication:https://doi.org/10.1038/s41586-023-05771-9
PubMed:View item in PubMed

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