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RESEARCH PRODUCT
The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients.
Konstantin FischerKlaus KluckKlaus KluckToni T. SeppäläToni T. SeppäläRobert HüneburgGabriela MösleinNina NeliusGeorg Martin HaagRichard GallonGillian M. BorthwickMaarit AhtiainenJacob NattermannLelia WagnerJohn BurnJan BudcziesJan BudcziesMatthias KloorHendrik BläkerAysel AhadovaGlen KristiansenD. Timothy BishopBen HartogMagnus Von Knebel DoeberitzPauline L. PfudererSvenja KösegiNico MüllerFabian EchterdiekAlbrecht StenzingerAlbrecht StenzingerMartina KirchnerElena BuschOliver HommerdingLena BohaumilitzkyJukka-pekka Mecklinsubject
MaleCD3 ComplexColorectal cancerT-LymphocytesCD8-Positive T-LymphocytesT-Lymphocytes Regulatory0302 clinical medicineIntestinal MucosaMismatch Repair Endonuclease PMS2Aged 80 and over0303 health sciencesbiologyGastroenterologyFOXP3Forkhead Transcription FactorsMiddle AgedLynch syndrome3. Good healthDNA-Binding Proteinsmedicine.anatomical_structureMutS Homolog 2 Protein030220 oncology & carcinogenesisFemaleMicrosatellite InstabilityMutL Protein Homolog 1AdultHeterozygoteColonT cellCD303 medical and health sciencesYoung AdultImmune systemmedicineHumansLymphocyte Count030304 developmental biologyAgedHepatologybusiness.industryCarcinomaRectumCancerMicrosatellite instabilitymedicine.diseaseColorectal Neoplasms Hereditary NonpolyposisCancer researchbiology.proteinbusinessTranscriptomedescription
ABSTRACT Background and aims Due 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 219, 233 and 201 formalin-fixed paraffin-embedded (FFPE) normal colonic mucosa tissue sections from CRC patients and LS cancer-free carriers and 26, 22 and 19 LS CRCs, respectively. CD3-positive T cells were also quantified in an independent cohort of 97 FFPE normal rectal mucosa tissue sections from LS carriers enrolled on the CAPP2 clinical trial. The expression of 770 immune-relevant genes was analyzed in a subset of samples using the NanoString nCounter platform. Results LS normal mucosa specimens showed significantly elevated CD3-, FOXP3- and CD8-positive T cell densities compared to non-LS controls. 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. Conclusion 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-06-23 | Gastroenterology |