TY - JOUR
T1 - Antibodies against endogenous retroviruses promote lung cancer immunotherapy
AU - TRACERx Consortium
AU - CAPTURE Consortium
AU - Ng, Kevin W.
AU - Boumelha, Jesse
AU - Enfield, Katey S.S.
AU - Almagro, Jorge
AU - Cha, Hongui
AU - Pich, Oriol
AU - Karasaki, Takahiro
AU - Moore, David A.
AU - Salgado, Roberto
AU - Sivakumar, Monica
AU - Young, George
AU - Molina-Arcas, Miriam
AU - de Carné Trécesson, Sophie
AU - Anastasiou, Panayiotis
AU - Fendler, Annika
AU - Au, Lewis
AU - Shepherd, Scott T.C.
AU - Martínez-Ruiz, Carlos
AU - Puttick, Clare
AU - Black, James R.M.
AU - Watkins, Thomas B.K.
AU - Kim, Hyemin
AU - Shim, Seohee
AU - Faulkner, Nikhil
AU - Attig, Jan
AU - Veeriah, Selvaraju
AU - Magno, Neil
AU - Ward, Sophia
AU - Frankell, Alexander M.
AU - Al Bakir, Maise
AU - Lim, Emilia L.
AU - Hill, Mark S.
AU - Wilson, Gareth A.
AU - Cook, Daniel E.
AU - Birkbak, Nicolai J.
AU - Behrens, Axel
AU - Yousaf, Nadia
AU - Popat, Sanjay
AU - Hackshaw, Allan
AU - Rowan, Andrew
AU - Huebner, Ariana
AU - Campbell, Brittany B.
AU - Bailey, Chris
AU - Lee, Claudia
AU - Biswas, Dhruva
AU - Colliver, Emma
AU - Athanasopoulou, Foteini
AU - Van Loo, Peter
AU - Pan, Xiaoxi
AU - Yuan, Yinyin
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/4/20
Y1 - 2023/4/20
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-023-05771-9
DO - 10.1038/s41586-023-05771-9
M3 - Article
C2 - 37046094
AN - SCOPUS:85152879722
SN - 0028-0836
VL - 616
SP - 563
EP - 573
JO - Nature
JF - Nature
IS - 7957
ER -