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

Abstract

BACKGROUND & 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.

• Authors: Lena Bohaumilitzky, Klaus Kluck, Robert Hüneburg, Richard Gallon, Jacob Nattermann, Martina Kirchner, Glen Kristiansen, Oliver Hommerding, Pauline L Pfuderer, Lelia Wagner, Fabian Echterdiek, Svenja Kösegi, Nico Müller, Konstantin Fischer, Nina Nelius, Ben Hartog, Gillian Borthwick, Elena Busch, Georg Martin Haag, Hendrik Bläker, Gabriela Möslein, Magnus von Knebel Doeberitz, Toni T Seppälä, Maarit Ahtiainen, Jukka-Pekka Mecklin, D Timothy Bishop, John Burn, Albrecht Stenzinger, Jan Budczies, Matthias Kloor, Aysel Ahadova
• Journal: Gastroenterology (Gastroenterology) Vol. 162 Issue 3 Pg. 907-919.e10 (03 2022) ISSN: 1528-0012 [Electronic] United States
• PMID: 34863788 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• CD3 Complex
• DNA-Binding Proteins
• FOXP3 protein, human
• Forkhead Transcription Factors
• G-T mismatch-binding protein
• MLH1 protein, human
• PMS2 protein, human
• MSH2 protein, human
• Mismatch Repair Endonuclease PMS2
• MutL Protein Homolog 1
• MutS Homolog 2 Protein

Topics

• Adult
• Aged
• Aged, 80 and over
• CD3 Complex (metabolism)
• CD8-Positive T-Lymphocytes (pathology)
• Carcinoma (genetics, immunology, pathology)
• Colon (immunology)
• Colorectal Neoplasms, Hereditary Nonpolyposis (genetics, immunology, pathology)
• DNA-Binding Proteins (genetics)
• Female
• Forkhead Transcription Factors (metabolism)
• Heterozygote
• Humans
• Intestinal Mucosa (immunology, pathology)
• Lymphocyte Count
• Male
• Microsatellite Instability
• Middle Aged
• Mismatch Repair Endonuclease PMS2 (genetics)
• MutL Protein Homolog 1 (genetics)
• MutS Homolog 2 Protein (genetics)
• Rectum (immunology)
• T-Lymphocytes (metabolism, pathology)
• T-Lymphocytes, Regulatory (metabolism, pathology)
• Transcriptome
• Young Adult