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The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients

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.

Publication metadata

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


DOI: 10.1053/j.gastro.2021.11.029

PubMed id: 34863788


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