title: Low density of FOXP3-positive T cells in normal colonic mucosa is related to the presence of beta2-microglobulin mutations in Lynch syndrome-associated colorectal cancer.
abstract: Microsatellite instability (MSI-H) is caused by DNA mismatch repair deficiency and occurs in 15% of colorectal cancers. MSI-H cancers generate highly immunogenic frameshift peptide (FSP) antigens, which elicit pronounced local immune responses. A subset of MSI-H colorectal cancers develops in frame of Lynch syndrome, which represents an ideal human model for studying the concept of immunoediting. Immunoediting describes how continuous anti-tumoral immune surveillance of the host eventually leads to the selection of tumor cells that escape immune cell recognition and destruction. Between 30 and 40% of Lynch syndrome-associated colorectal cancers display loss of HLA class I antigen expression as a result of Beta2-microglobulin (B2M) mutations. WhetherB2Mmutations result from immunoediting has been unknown. To address this question, we relatedB2Mmutation status of Lynch syndrome-associated colorectal cancer specimens (n = 30) to CD3-positive, CD8-positive and FOXP3-positive T cell infiltration in both tumor and normal mucosa. No significant correlation betweenB2Mmutations and immune cell infiltration was observed in tumor tissue. However, FOXP3-positive T cell infiltration was significantly lower in normal mucosa adjacent toB2M-mutant (mt) compared toB2M-wild type (wt) tumors (mean: 0.98% FOXP3-positive area/region of interest (ROI) inB2M-wt vs. 0.52% FOXP3-positive area/ROI inB2M-mt,p= 0.023). Our results suggest that in the absence of immune-suppressive regulatory T cells (Treg), the outgrowth of less immunogenicB2M-mt tumor cells is favored. This finding supports the immunoediting concept in human solid cancer development and indicates a critical role of the immune milieu in normal colonic mucosa for the course of disease.
authors.affiliation: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany, and Molecular Medicine Partnership Unit, University Hospital Heidelberg and EMBL Heidelberg , Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Echterdiek
authors.affiliation: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany, and Molecular Medicine Partnership Unit, University Hospital Heidelberg and EMBL Heidelberg , Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Janikovits
authors.affiliation: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany, and Molecular Medicine Partnership Unit, University Hospital Heidelberg and EMBL Heidelberg , Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Staffa
authors.affiliation: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany, and Molecular Medicine Partnership Unit, University Hospital Heidelberg and EMBL Heidelberg , Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Müller
authors.affiliation: Hamamatsu Tissue Imaging and Analysis (TIGA) Center , Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lahrmann
authors.affiliation: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany, and Molecular Medicine Partnership Unit, University Hospital Heidelberg and EMBL Heidelberg , Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Frühschütz
authors.affiliation: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany, and Molecular Medicine Partnership Unit, University Hospital Heidelberg and EMBL Heidelberg , Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hartog
authors.affiliation: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany, and Molecular Medicine Partnership Unit, University Hospital Heidelberg and EMBL Heidelberg , Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Nelius
authors.affiliation: Division of Biostatistics, DKFZ (German Cancer Research Center) , Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Department of General, Visceral and Accident Surgery, University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Tariverdian
authors.affiliation: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany, and Molecular Medicine Partnership Unit, University Hospital Heidelberg and EMBL Heidelberg , Germany.
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel Doeberitz
authors.affiliation: Hamamatsu Tissue Imaging and Analysis (TIGA) Center , Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany, and Molecular Medicine Partnership Unit, University Hospital Heidelberg and EMBL Heidelberg , Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
keywords: Beta2-microglobulin; Lynch syndrome; colorectal cancer; hereditary cancer; immunoediting; microsatellite instability; regulatory T cells