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 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

doi:10.1053/j.gastro.2021.11.029

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 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

39 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 language	English
Pages (from-to)	907-919.e10
Journal	Gastroenterology
Volume	162
Issue number	3
DOIs	https://doi.org/10.1053/j.gastro.2021.11.029
Publication status	Published - Mar 2022
Externally published	Yes
Publication type	A1 Journal article-refereed

Funding

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. 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. 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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Colorectal Cancer
Immune Infiltration
Lynch Syndrome
Normal Mucosa
Tumor Risk

ASJC Scopus subject areas

Hepatology
Gastroenterology

Access to Document

10.1053/j.gastro.2021.11.029

Cite this

Bohaumilitzky, L., Kluck, K., Hüneburg, R., Gallon, R., Nattermann, J., Kirchner, M., Kristiansen, G., Hommerding, O., Pfuderer, P. L., Wagner, L., Echterdiek, F., Kösegi, S., Müller, N., Fischer, K., Nelius, N., Hartog, B., Borthwick, G., Busch, E., Haag, G. M., ... Ahadova, A. (2022). The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients. Gastroenterology, 162(3), 907-919.e10. https://doi.org/10.1053/j.gastro.2021.11.029

@article{80d91ed314ab4444bac93752f8e10957,

title = "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.",

keywords = "Colorectal Cancer, Immune Infiltration, Lynch Syndrome, Normal Mucosa, Tumor Risk",

author = "Lena Bohaumilitzky and Klaus Kluck and Robert H{\"u}neburg and Richard Gallon and Jacob Nattermann and Martina Kirchner and Glen Kristiansen and Oliver Hommerding and Pfuderer, \{Pauline L.\} and Lelia Wagner and Fabian Echterdiek and Svenja K{\"o}segi and Nico M{\"u}ller and Konstantin Fischer and Nina Nelius and Ben Hartog and Gillian Borthwick and Elena Busch and Haag, \{Georg Martin\} and Hendrik Bl{\"a}ker and Gabriela M{\"o}slein and \{von Knebel Doeberitz\}, Magnus and Sepp{\"a}l{\"a}, \{Toni T.\} and Maarit Ahtiainen and Mecklin, \{Jukka Pekka\} and Bishop, \{D. Timothy\} and John Burn and Albrecht Stenzinger and Jan Budczies and Matthias Kloor and Aysel Ahadova",

note = "Funding Information: Funding This study was performed with grant support from Else Kr{\"o}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. Funding Information: Conflicts of interest Dr H{\"u}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{\"a}l{\"a} 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: {\textcopyright} 2022 AGA Institute",

year = "2022",

month = mar,

doi = "10.1053/j.gastro.2021.11.029",

language = "English",

volume = "162",

pages = "907--919.e10",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "3",

}

Bohaumilitzky, L, Kluck, K, Hüneburg, R, Gallon, R, Nattermann, J, Kirchner, M, Kristiansen, G, Hommerding, O, Pfuderer, PL, Wagner, L, Echterdiek, F, Kösegi, S, Müller, N, Fischer, K, Nelius, N, Hartog, B, Borthwick, G, Busch, E, Haag, GM, Bläker, H, Möslein, G, von Knebel Doeberitz, M, Seppälä, TT, Ahtiainen, M, Mecklin, JP, Bishop, DT, Burn, J, Stenzinger, A, Budczies, J, Kloor, M & Ahadova, A 2022, 'The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients', Gastroenterology, vol. 162, no. 3, pp. 907-919.e10. https://doi.org/10.1053/j.gastro.2021.11.029

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 -

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

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