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Lookup NU author(s): Dr Richard Gallon, Dr Gillian Borthwick, Professor Sir John BurnORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2021 AGA InstituteBackground & Aims: Owing to the high load of immunogenic frameshift neoantigens, tumors arising in individuals with Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, are characterized by a pronounced immune infiltration. However, the immune status of normal colorectal mucosa in LS is not well characterized. We assessed the immune infiltrate in tumor-distant normal colorectal mucosa from LS CRC patients, sporadic microsatellite-unstable (MSI) and microsatellite-stable (MSS) CRC patients, and cancer-free LS carriers. Methods: CD3-positive, FOXP3-positive, and CD8-positive T cells were quantified in, respectively, 219, 233, and 201 formalin-fixed paraffin-embedded (FFPE) normal colonic mucosa tissue sections from CRC patients and cancer-free LS carriers and 26, 22, and 19 LS CRCs. CD3-positive T cells were also quantified in an independent cohort of 97 FFPE normal rectal mucosa tissue sections from LS carriers enrolled in the CAPP2 clinical trial. The expression of 770 immune-relevant genes was analyzed in a subset of samples with the use of the NanoString nCounter platform. Results: LS normal mucosa specimens showed significantly elevated CD3-, FOXP3-, and CD8-positive T-cell densities compared with non-LS control specimens. Gene expression profiling and cluster analysis revealed distinct immune profiles in LS carrier mucosa with and without cancer manifestation. Long-term follow-up of LS carriers within the CAPP2 trial found a correlation between mucosal T-cell infiltrate and time to subsequent tumor occurrence. Conclusions: LS carriers show elevated mucosal T-cell infiltration even in the absence of cancer. The normal mucosa immune profile may be a temporary or permanent tumor risk modifier in LS carriers.
Author(s): Bohaumilitzky L, Kluck K, Huneburg R, Gallon R, Nattermann J, Kirchner M, Kristiansen G, Hommerding O, Pfuderer PL, Wagner L, Echterdiek F, Kosegi S, Muller N, Fischer K, Nelius N, Hartog B, Borthwick G, Busch E, Haag GM, Blaker H, Moslein G, von Knebel Doeberitz M, Seppala TT, Ahtiainen M, Mecklin J-P, Bishop DT, Burn J, Stenzinger A, Budczies J, Kloor M, Ahadova A
Publication type: Article
Publication status: Published
Journal: Gastroenterology
Year: 2022
Volume: 162
Issue: 3
Pages: 907-919.e10
Print publication date: 01/03/2022
Online publication date: 01/12/2021
Acceptance date: 22/11/2021
Date deposited: 27/10/2022
ISSN (print): 0016-5085
ISSN (electronic): 1528-0012
Publisher: W.B. Saunders
URL: https://doi.org/10.1053/j.gastro.2021.11.029
DOI: 10.1053/j.gastro.2021.11.029
PubMed id: 34863788
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