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

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 BläkerGabriela 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

Research output: Contribution to journalArticleScientificpeer-review

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)907-919.e10
JournalGastroenterology
Volume162
Issue number3
DOIs
Publication statusPublished - Mar 2022
Externally publishedYes
Publication typeA1 Journal article-refereed

Keywords

  • Colorectal Cancer
  • Immune Infiltration
  • Lynch Syndrome
  • Normal Mucosa
  • Tumor Risk

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Fingerprint

Dive into the research topics of 'The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients'. Together they form a unique fingerprint.

Cite this