Abstract

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.

Tertiary lymphoid structures (TLS) are associated with a reduced risk of cancer recurrence and improved response to immune checkpoint blockade in several tumor types. Here the authors identify L1CAM as a marker for mature TLS and show that the presence of TLS is associated with favorable prognosis in patients with endometrial cancer from the PORTEC-3 trial.

Details

Title
Tertiary lymphoid structures critical for prognosis in endometrial cancer patients
Author
Nanda, Horeweg 1   VIAFID ORCID Logo  ; Workel, Hagma H 2 ; Loiero Dominik 3   VIAFID ORCID Logo  ; Church, David N 4 ; Vermij, Lisa 5 ; Léon-Castillo, Alicia 5 ; Krog, Ricki T 6   VIAFID ORCID Logo  ; de Boer Stephanie M 1 ; Nout, Remi A 7 ; Powell, Melanie E 8 ; Mileshkin, Linda R 9 ; MacKay, Helen 10 ; Leary, Alexandra 11 ; Singh Naveena 12 ; Jürgenliemk-Schulz, Ina M 13 ; Smit Vincent T H B M 5 ; Creutzberg, Carien L 1   VIAFID ORCID Logo  ; Koelzer, Viktor H 14   VIAFID ORCID Logo  ; Nijman, Hans W 2 ; Bosse Tjalling 5 ; de Bruyn Marco 2   VIAFID ORCID Logo 

1  Leiden University Medical Center, Department of Radiation Oncology, Leiden, the Netherlands (GRID:grid.10419.3d) (ISNI:0000000089452978) 
2  University Medical Center Groningen, Department of Gynaecologic Oncology, Groningen, the Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598) 
3  University Hospital Zurich, University of Zurich, Department of Pathology and Molecular Pathology, Zurich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650) 
4  University of Oxford, Wellcome Centre for Human Genetics, Oxford, United Kingdom (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); Oxford University Hospitals NHS Foundation Trust, Oxford NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom (GRID:grid.410556.3) (ISNI:0000 0001 0440 1440) 
5  Leiden University Medical Center, Department of Pathology, Leiden, the Netherlands (GRID:grid.10419.3d) (ISNI:0000000089452978) 
6  Leiden University Medical Center, Department of Pathology, Leiden, the Netherlands (GRID:grid.10419.3d) (ISNI:0000000089452978); Leiden University Medical Center, Department Surgery, Leiden, the Netherlands (GRID:grid.10419.3d) (ISNI:0000000089452978) 
7  Erasmus MC Cancer Institute, Department of Radiotherapy, Rotterdam, the Netherlands (GRID:grid.508717.c) (ISNI:0000 0004 0637 3764) 
8  Barts Health NHS Trust, Department of Clinical Oncology, London, United Kingdom (GRID:grid.139534.9) (ISNI:0000 0001 0372 5777) 
9  Peter MacCallum Cancer Centre, Department of Medical Oncology, Melbourne, Australia (GRID:grid.1055.1) (ISNI:0000000403978434) 
10  Sunnybrook Odette Cancer Centre, Division of Medical Oncology and Hematology, Toronto, Canada (GRID:grid.413104.3) (ISNI:0000 0000 9743 1587) 
11  Gustave Roussy, Department of Medical Oncology, Villejuif, France (GRID:grid.14925.3b) (ISNI:0000 0001 2284 9388) 
12  Barts Health NHS Trust, Department of Pathology, London, United Kingdom (GRID:grid.139534.9) (ISNI:0000 0001 0372 5777) 
13  University Medical Center Utrecht, Department of Radiation Oncology, Utrecht, the Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352) 
14  University Hospital Zurich, University of Zurich, Department of Pathology and Molecular Pathology, Zurich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650); University of Oxford, Department of Oncology and Nuffield Department of Medicine, Oxford, United Kingdom (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-29040-x
ProQuest document ID
2640587008
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.