TY - JOUR
T1 - Tertiary lymphoid structures critical for prognosis in endometrial cancer patients
AU - Horeweg, Nanda
AU - Workel, Hagma H.
AU - Loiero, Dominik
AU - Church, David N.
AU - Vermij, Lisa
AU - Léon-Castillo, Alicia
AU - Krog, Ricki T.
AU - de Boer, Stephanie M.
AU - Nout, Remi A.
AU - Powell, Melanie E.
AU - Mileshkin, Linda R.
AU - MacKay, Helen
AU - Leary, Alexandra
AU - Singh, Naveena
AU - Jürgenliemk-Schulz, Ina M.
AU - Smit, Vincent T.H.B.M.
AU - Creutzberg, Carien L.
AU - Koelzer, Viktor H.
AU - Nijman, Hans W.
AU - Bosse, Tjalling
AU - de Bruyn, Marco
AU - Horeweg, Nanda
AU - Church, David N.
AU - de Boer, Stephanie M.
AU - Nout, Remi A.
AU - Powell, Melanie E.
AU - MacKay, Helen
AU - Leary, Alexandra
AU - Singh, Naveena
AU - Creutzberg, Carien L.
AU - Nijman, Hans W.
AU - Bosse, Tjalling
AU - de Bruyn, Marco
N1 - Funding Information:
Dr. Horeweg reports outside of the submitted work to have received research grants from the Dutch Cancer Society (KWF-2021-13400, KWF-2021-13404). Dr. Church is funded by a Cancer Research UK Advanced Clinician Scientist Fellowship (C26642/A27963) and reports to be part of the advisory board for MSD. Prof. Nout, Dr. Bosse and Prof. Creutzberg report to have received a grant from the Dutch Cancer Society for the PORTEC-3 trial (KWF 2018-1-11629). Prof. Koelzer reports grants from Promedica Foundation (F-87701-41-01) during the conduct of the study and having served as an invited speaker on behalf of Indica Labs. Dr. de Bruyn reports, outside the submitted work, having received grants from the Dutch Cancer Society (KWF), grants from the European Research Council (ERC), grants from Health Holland, grants from DCPrime, non-financial support from BioNTech, non-financial support from Surflay, non-financial support from MSD, grants and non-financial support from Vicinivax. In addition, dr. de Bruyn has grants and non-financial support from Aduro Biotech, in part relating to a patent for Antibodies targeting CD103 (de Bruyn et al. No. 62/704,258). The remaining authors declare no competing interests.
Funding Information:
We gratefully acknowledge the PORTEC-3 study group and TransPORTEC consortium for their contribution to the conduct of the PORTEC-3 trial and the establishment of the TransPORTEC biobank. A list of the members of these consortia is provided in the Supplementary Information. The authors would also like to thank Nienke van Rooij, Diana Spierings and Bart Eggen for their support in the acquisition of the single cell RNA sequencing data. This work was supported by the Dutch Cancer Society (project grants: LUMC KWF-2018-1-11629, RUG 2015-7235 and 8232-21648). This work was supported by The Oxford NIHR Comprehensive Biomedical Research Centre (BRC) and WHG core funding from the Wellcome Trust (203141/Z/16/Z). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health. This is an academic-sponsored, investigator-initiated study, the funding bodies had no role in the study design, data collection, analysis or manuscript writing.
Funding Information:
We gratefully acknowledge the PORTEC-3 study group and TransPORTEC consortium for their contribution to the conduct of the PORTEC-3 trial and the establishment of the TransPORTEC biobank. A list of the members of these consortia is provided in the Supplementary Information. The authors would also like to thank Nienke van Rooij, Diana Spierings and Bart Eggen for their support in the acquisition of the single cell RNA sequencing data. This work was supported by the Dutch Cancer Society (project grants: LUMC KWF-2018-1-11629, RUG 2015-7235 and 8232-21648). This work was supported by The Oxford NIHR Comprehensive Biomedical Research Centre (BRC) and WHG core funding from the Wellcome Trust (203141/Z/16/Z). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health. This is an academic-sponsored, investigator-initiated study, the funding bodies had no role in the study design, data collection, analysis or manuscript writing.
Publisher Copyright:
© 2022, The Author(s).
© 2022. The Author(s).
PY - 2022/3/16
Y1 - 2022/3/16
N2 - B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigate the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells shows presence of naïve B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis shows association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence show L1CAM expression in mature TLS, independent of L1CAM expression in the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank are evaluated, TLS are found in 19%. L1CAM expressing TLS are most common in mismatch-repair deficient (29/127, 23%) and polymerase-epsilon mutant EC (24/47, 51%). Multivariable Cox regression analysis shows strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker.
AB - B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigate the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells shows presence of naïve B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis shows association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence show L1CAM expression in mature TLS, independent of L1CAM expression in the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank are evaluated, TLS are found in 19%. L1CAM expressing TLS are most common in mismatch-repair deficient (29/127, 23%) and polymerase-epsilon mutant EC (24/47, 51%). Multivariable Cox regression analysis shows strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker.
KW - Endometrial Neoplasms/pathology
KW - Female
KW - Germinal Center/metabolism
KW - Humans
KW - Immunohistochemistry
KW - Neural Cell Adhesion Molecule L1
KW - Tertiary Lymphoid Structures/genetics
UR - http://www.scopus.com/inward/record.url?scp=85126703650&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-29040-x
DO - 10.1038/s41467-022-29040-x
M3 - Article
C2 - 35296668
AN - SCOPUS:85126703650
SN - 2041-1723
VL - 13
SP - 1
EP - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1373
ER -