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 language | English |
---|---|
Pages (from-to) | 907-919.e10 |
Journal | Gastroenterology |
Volume | 162 |
Issue number | 3 |
DOIs | |
Publication status | Published - Mar 2022 |
Externally published | Yes |
Publication type | A1 Journal article-refereed |
Keywords
- Colorectal Cancer
- Immune Infiltration
- Lynch Syndrome
- Normal Mucosa
- Tumor Risk
ASJC Scopus subject areas
- Hepatology
- Gastroenterology
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In: Gastroenterology, Vol. 162, No. 3, 03.2022, p. 907-919.e10.
Research output: Contribution to journal › Article › Scientific › peer-review
TY - JOUR
T1 - The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients
AU - Bohaumilitzky, Lena
AU - Kluck, Klaus
AU - Hüneburg, Robert
AU - Gallon, Richard
AU - Nattermann, Jacob
AU - Kirchner, Martina
AU - Kristiansen, Glen
AU - Hommerding, Oliver
AU - Pfuderer, Pauline L.
AU - Wagner, Lelia
AU - Echterdiek, Fabian
AU - Kösegi, Svenja
AU - Müller, Nico
AU - Fischer, Konstantin
AU - Nelius, Nina
AU - Hartog, Ben
AU - Borthwick, Gillian
AU - Busch, Elena
AU - Haag, Georg Martin
AU - Bläker, Hendrik
AU - Möslein, Gabriela
AU - von Knebel Doeberitz, Magnus
AU - Seppälä, Toni T.
AU - Ahtiainen, Maarit
AU - Mecklin, Jukka Pekka
AU - Bishop, D. Timothy
AU - Burn, John
AU - Stenzinger, Albrecht
AU - Budczies, Jan
AU - Kloor, Matthias
AU - Ahadova, Aysel
N1 - Funding Information: Funding This study was performed with grant support from Else Kröner-Fresenius Stiftung, Cancer Research UK (CAPP2 and Catalyst Award C569/A24991), European Union, MRC, NIHR, Bayer Pharma, The Barbour Foundation (Charity Commission for England and Wales no. 328081), Finnish Medical Foundation, Emil Aaltonen Foundation, Cancer Society Finland, Jane and Aatos Erkko Foundation, iCAN Digital Precision Cancer Medicine Flagship, and Sigrid Juselius Foundation. The funding bodies had no role in the study design, collection, analysis, or interpretation of the data. Funding Information: Conflicts of interest Dr Hüneburg reports an equipment loan from FujiFilm and is a consultant for Cancer Prevention Pharmaceuticals. Dr Haag reports consulting or advisory roles for Bristol-Myers Squibb, MSD Sharp & Dohme, EsoCap, and Lilly, honoraria from Servier, MSD Sharp & Dohme, Lilly, and Targos, research funding from Nordic Pharma, Taiho Pharmaceutical, and MSD Sharp & Dohme, and travel and accommodations from Bristol-Myers Squibb, Lilly, and Servier, outside the submitted work. Dr Seppälä is CEO and co-owner of Healthfund Finland and reports an interview honorarium from Boehringer Ingelheim Finland. Martina Kirchner reports grants from QuIP, outside the submitted work. The other authors declare no conflicts. Funding Information: The excellent technical assistance of Petra H?fler, Lena Ehret-Ma?holder, and Vera Fuchs is gratefully acknowledged. Lena Bohaumilitzky, MSc (Conceptualization: Equal; Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Software: Equal; Validation: Equal; Visualization: Equal; Writing ? original draft: Equal; Writing ? review & editing: Equal); Klaus Kluck, MSc (Data curation: Equal; Formal analysis: Equal; Investigation: Supporting; Methodology: Equal; Software: Equal; Validation: Equal; Visualization: Equal; Writing ? original draft: Equal; Writing ? review & editing: Supporting); Robert H?neburg, MD (Conceptualization: Supporting; Investigation: Supporting; Resources: Equal; Writing ? original draft: Supporting; Writing ? review & editing: Supporting); Richard Gallon, PhD (Conceptualization: Supporting; Data curation: Equal; Formal analysis: Equal; Funding acquisition: Supporting; Investigation: Equal; Resources: Equal; Writing ? original draft: Equal; Writing ? review & editing: Supporting); Jacob Nattermann, MD (Conceptualization: Supporting; Investigation: Supporting; Resources: Equal; Writing ? original draft: Supporting; Writing ? review & editing: Supporting); Martina Kirchner, PhD (Formal analysis: Equal; Investigation: Supporting; Methodology: Equal; Writing ? original draft: Supporting; Writing ? review & editing: Supporting); Glen Kristiansen, MD (Data curation: Supporting; Resources: Equal; Writing ? review & editing: Supporting); Oliver Hommerding, MD (Data curation: Supporting; Resources: Equal; Writing ? review & editing: Supporting); Pauline L. Pfuderer, Bsc (Formal analysis: Supporting; Investigation: Supporting; Software: Supporting; Visualization: Supporting; Writing ? review & editing: Supporting); Lelia Wagner, BSc (Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Writing ? review & editing: Supporting); Fabian Echterdiek, MD (Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Writing ? review & editing: Supporting); Svenja K?segi, BSc (Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Writing ? review & editing: Supporting); Nico M?ller, BSc (Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Writing ? review & editing: Supporting); Konstantin Fischer, BSc (Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Writing ? review & editing: Supporting); Nina Nelius, Ms (Data curation: Supporting; Formal analysis: Supporting; Writing ? review & editing: Supporting); Ben Hartog, PhD (Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Resources: Supporting; Writing ? review & editing: Supporting); Gillian Borthwick, PhD (Funding acquisition: Supporting; Project administration: Supporting; Resources: Supporting; Writing ? review & editing: Supporting); Elena Busch, MD (Investigation: Supporting; Methodology: Supporting; Resources: Supporting; Writing ? review & editing: Supporting); Georg Martin Haag, MD (Investigation: Supporting; Methodology: Supporting; Resources: Supporting; Writing ? review & editing: Supporting); Henrik Bl?ker, MD (Investigation: Supporting; Methodology: Supporting; Resources: Supporting; Writing ? review & editing: Supporting); Gabriela M?slein, MD (Investigation: Supporting; Resources: Supporting; Writing ? review & editing: Supporting); Magnus von Knebel Doeberitz, MD (Conceptualization: Equal; Funding acquisition: Equal; Investigation: Supporting; Resources: Equal; Supervision: Supporting; Writing ? original draft: Supporting; Writing ? review & editing: Supporting); Toni T. Sepp?l?, MD (Conceptualization: Supporting; Funding acquisition: Equal; Investigation: Supporting; Resources: Equal; Writing ? original draft: Supporting; Writing ? review & editing: Supporting); Maarit Ahtiainen, PhD (Data curation: Supporting; Methodology: Supporting; Project administration: Supporting; Resources: Equal; Writing ? review & editing: Supporting); Jukka-Pekka Mecklin, MD (Conceptualization: Supporting; Funding acquisition: Equal; Investigation: Supporting; Resources: Equal; Writing ? review & editing: Supporting); D. Timothy Bishop, PhD (Investigation: Supporting; Methodology: Supporting; Resources: Equal; Writing ? review & editing: Supporting); John Burn, MD (Funding acquisition: Equal; Investigation: Equal; Methodology: Supporting; Resources: Equal; Supervision: Supporting; Writing ? review & editing: Supporting); Albrecht Stenzinger, MD (Conceptualization: Supporting; Formal analysis: Supporting; Investigation: Supporting; Resources: Equal; Supervision: Supporting; Writing ? review & editing: Supporting); Jan Budczies, PhD (Conceptualization: Supporting; Formal analysis: Equal; Investigation: Supporting; Methodology: Equal; Resources: Equal; Software: Equal; Supervision: Supporting; Writing ? original draft: Equal; Writing ? review & editing: Supporting); Matthias Kloor, MD (Conceptualization: Lead; Formal analysis: Equal; Funding acquisition: Equal; Investigation: Equal; Methodology: Equal; Resources: Equal; Supervision: Lead; Visualization: Supporting; Writing ? original draft: Equal; Writing ? review & editing: Equal); Aysel Ahadova, PhD (Conceptualization: Lead; Formal analysis: Equal; Funding acquisition: Equal; Investigation: Equal; Methodology: Equal; Resources: Supporting; Visualization: Lead; Writing ? original draft: Lead; Writing ? review & editing: Lead) Conflicts of interest Dr H?neburg reports an equipment loan from FujiFilm and is a consultant for Cancer Prevention Pharmaceuticals. Dr Haag reports consulting or advisory roles for Bristol-Myers Squibb, MSD Sharp & Dohme, EsoCap, and Lilly, honoraria from Servier, MSD Sharp & Dohme, Lilly, and Targos, research funding from Nordic Pharma, Taiho Pharmaceutical, and MSD Sharp & Dohme, and travel and accommodations from Bristol-Myers Squibb, Lilly, and Servier, outside the submitted work. Dr Sepp?l? is CEO and co-owner of Healthfund Finland and reports an interview honorarium from Boehringer Ingelheim Finland. Martina Kirchner reports grants from QuIP, outside the submitted work. The other authors declare no conflicts. Funding This study was performed with grant support from Else Kr?ner-Fresenius Stiftung, Cancer Research UK (CAPP2 and Catalyst Award C569/A24991), European Union, MRC, NIHR, Bayer Pharma, The Barbour Foundation (Charity Commission for England and Wales no. 328081), Finnish Medical Foundation, Emil Aaltonen Foundation, Cancer Society Finland, Jane and Aatos Erkko Foundation, iCAN Digital Precision Cancer Medicine Flagship, and Sigrid Juselius Foundation. The funding bodies had no role in the study design, collection, analysis, or interpretation of the data. Publisher Copyright: © 2022 AGA Institute
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - Colorectal Cancer
KW - Immune Infiltration
KW - Lynch Syndrome
KW - Normal Mucosa
KW - Tumor Risk
U2 - 10.1053/j.gastro.2021.11.029
DO - 10.1053/j.gastro.2021.11.029
M3 - Article
C2 - 34863788
SN - 0016-5085
VL - 162
SP - 907-919.e10
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -