TY - JOUR
T1 - Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer
AU - Posch, Florian
AU - Silina, Karina
AU - Leibl, Sebastian
AU - Mündlein, Axel
AU - Moch, Holger
AU - Siebenhüner, Alexander
AU - Samaras, Panagiotis
AU - Riedl, Jakob
AU - Stotz, Michael
AU - Szkandera, Joanna
AU - Stöger, Herbert
AU - Pichler, Martin
AU - Stupp, Roger
AU - van den Broek, Maries
AU - Schraml, Peter
AU - Gerger, Armin
AU - Petrausch, Ulf
AU - Winder, Thomas
N1 - Funding Information:
This work was supported by the Forschungskredit of the University of Zurich (project number K-84901-01-01), the Swiss National Science Foundation (SNSF), the Sciex Foundation, the Science Foundation for Oncology (SFO), the Cancer League Zurich, the Novartis Research Foundation, the University Research Priority Program (URPP) “Translational Cancer Research”, Swiss Cancer League (reference number F-87701-31-01), and the Cancer League Zurich. We thank Susanne Dettwiler (lead bioanalytical technician of the University of Zurich biobank) for valuable technical assistance. Further, we are grateful to Dr. Sylvia Gusel (Division of Oncology, Medical University of Graz) for help with electronic clinical data management, and Dr. Sebastian Fuchs (Biobank, Medical University of Graz) for assistance with biospecimen retrieval.
Publisher Copyright:
© 2018 The Author(s). Published with license by Taylor & Francis Group, LLC © 2018, © Florian Posch, Karina Silina, Sebastian Leibl, Axel Mündlein, Holger Moch, Alexander Siebenhüner, Panagiotis Samaras, Jakob Riedl, Michael Stotz, Joanna Szkandera, Herbert Stöger, Martin Pichler, Roger Stupp, Maries van den Broek, Peter Schraml, Armin Gerger, Ulf Petrausch and Thomas Winder.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Tertiary lymphoid structures (TLS) are associated with favorable outcome in non-metastatic colorectal carcinoma (nmCRC), but the dynamics of TLS maturation and its association with effective anti-tumor immune surveillance in nmCRC are unclear. Here, we hypothesized that not only the number of TLS but also their composition harbors information on recurrence risk in nmCRC. In a comprehensive molecular, tissue, laboratory, and clinical analysis of 109 patients with stage II/III nmCRC, we assessed TLS numbers and degree of maturation in surgical specimens by multi-parameter immunofluorescence of follicular dendritic cell (FDC) and germinal center (GC) markers. TLS formed in most tumors and were significantly more prevalent in highly-microsatellite-instable (MSI-H) and/or BRAF-mutant nmCRC. We could distinguish three sequential TLS maturation stages which were characterized by increasing prevalence of FDCs and mature B-cells: [1] Early TLS, composed of dense lymphocytic aggregates without FDCs, [2] Primary follicle-like TLS, having FDCs but no GC reaction, and [3] Secondary follicle-like TLS, having an active GC reaction. A simple integrated TLS immunoscore reflecting these parameters identified a large subgroup of nmCRC patients with a very low risk of recurrence independently of clinical co-variables such as ECOG performance status, age, stage, and adjuvant chemotherapy. We conclude that (1) mismatch repair and BRAF mutation status are associated with the formation of TLS in nmCRC, (2) TLS formation in nmCRC follows sequential maturation steps, culminating in germinal center formation, and (3) this maturation process harbors important prognostic information on the risk of disease recurrence.
AB - Tertiary lymphoid structures (TLS) are associated with favorable outcome in non-metastatic colorectal carcinoma (nmCRC), but the dynamics of TLS maturation and its association with effective anti-tumor immune surveillance in nmCRC are unclear. Here, we hypothesized that not only the number of TLS but also their composition harbors information on recurrence risk in nmCRC. In a comprehensive molecular, tissue, laboratory, and clinical analysis of 109 patients with stage II/III nmCRC, we assessed TLS numbers and degree of maturation in surgical specimens by multi-parameter immunofluorescence of follicular dendritic cell (FDC) and germinal center (GC) markers. TLS formed in most tumors and were significantly more prevalent in highly-microsatellite-instable (MSI-H) and/or BRAF-mutant nmCRC. We could distinguish three sequential TLS maturation stages which were characterized by increasing prevalence of FDCs and mature B-cells: [1] Early TLS, composed of dense lymphocytic aggregates without FDCs, [2] Primary follicle-like TLS, having FDCs but no GC reaction, and [3] Secondary follicle-like TLS, having an active GC reaction. A simple integrated TLS immunoscore reflecting these parameters identified a large subgroup of nmCRC patients with a very low risk of recurrence independently of clinical co-variables such as ECOG performance status, age, stage, and adjuvant chemotherapy. We conclude that (1) mismatch repair and BRAF mutation status are associated with the formation of TLS in nmCRC, (2) TLS formation in nmCRC follows sequential maturation steps, culminating in germinal center formation, and (3) this maturation process harbors important prognostic information on the risk of disease recurrence.
KW - Crohn's-like reaction
KW - colorectal cancer
KW - germinal center
KW - immunoscore
KW - recurrence
KW - risk factor
KW - structural equation model
KW - tertiary lymphoid structures
UR - http://www.scopus.com/inward/record.url?scp=85038392775&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85038392775&partnerID=8YFLogxK
U2 - 10.1080/2162402X.2017.1378844
DO - 10.1080/2162402X.2017.1378844
M3 - Article
C2 - 29416939
AN - SCOPUS:85038392775
VL - 7
JO - OncoImmunology
JF - OncoImmunology
SN - 2162-4011
IS - 2
M1 - e1378844
ER -