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Digital analysis and epigenetic regulation of the signature of rejection in colorectal cancer


Koelzer, Viktor H; Sokol, Lena; Zahnd, Stefan; Christe, Lucine; Dawson, Heather; Berger, Martin D; Inderbitzin, Daniel; Zlobec, Inti; Lugli, Alessandro (2017). Digital analysis and epigenetic regulation of the signature of rejection in colorectal cancer. OncoImmunology, 6(4):e1288330.

Abstract

The immune system plays a pivotal role in the development and progression of colorectal cancer (CRC). Tumor immune rejection has been previously linked to the activation of the interferon-stimulated genes (ISG) STAT1, IRF-5 and IRF-1. Specific immunoregulatory microRNAs (miRNAs) may impact the expression of these ISG in the tumor microenvironment. In this translational study, we develop a digital image analysis protocol to identify the ISG-gene expression signature and investigate miRNA expression in the immediate environment of invading cancer cells. Digital immunophenotyping was performed using next generation tissue microarrays from 241 well-characterized CRC patients and analyzed with clinicopathological and molecular information. Active ISG signaling in the tumor stroma differentiated an immune-activated (n = 178) and a quiescent (n = 43) phenotype. The activated phenotype was associated with high counts of intratumoral CD8+ cytotoxic T-lymphocytes (CTL; p = 0.007) and expression of the immune effector molecules granzyme B (p < 0.001) and perforin (p = 0.020). Immune-activated tumors also showed an elevated expression of the intercellular adhesion molecule-1 (ICAM-1, p = 0.006) which may facilitate CTL infiltration. Patients with immune-activated CRC had a considerably reduced risk of developing distant metastases (p = 0.001, OR = 0.034, 95%CI = 0.006–0.183). High expression of the immunoregulatory miR-34a and miR-93 corresponded to a 2–2.5-fold decrease of STAT1 (p = 0.006) and IRF-1 (p = 0.058), a feature more commonly seen in a quiescent microenvironment. Analysis of a combined ISG marker profile by digital pathology stratifies CRC patients into diametrically opposed immune phenotypes. Targeted inhibition of miRNAs within the tumor microenvironment may form a new strategy to stimulate the anti-tumoral immune response.

Abstract

The immune system plays a pivotal role in the development and progression of colorectal cancer (CRC). Tumor immune rejection has been previously linked to the activation of the interferon-stimulated genes (ISG) STAT1, IRF-5 and IRF-1. Specific immunoregulatory microRNAs (miRNAs) may impact the expression of these ISG in the tumor microenvironment. In this translational study, we develop a digital image analysis protocol to identify the ISG-gene expression signature and investigate miRNA expression in the immediate environment of invading cancer cells. Digital immunophenotyping was performed using next generation tissue microarrays from 241 well-characterized CRC patients and analyzed with clinicopathological and molecular information. Active ISG signaling in the tumor stroma differentiated an immune-activated (n = 178) and a quiescent (n = 43) phenotype. The activated phenotype was associated with high counts of intratumoral CD8+ cytotoxic T-lymphocytes (CTL; p = 0.007) and expression of the immune effector molecules granzyme B (p < 0.001) and perforin (p = 0.020). Immune-activated tumors also showed an elevated expression of the intercellular adhesion molecule-1 (ICAM-1, p = 0.006) which may facilitate CTL infiltration. Patients with immune-activated CRC had a considerably reduced risk of developing distant metastases (p = 0.001, OR = 0.034, 95%CI = 0.006–0.183). High expression of the immunoregulatory miR-34a and miR-93 corresponded to a 2–2.5-fold decrease of STAT1 (p = 0.006) and IRF-1 (p = 0.058), a feature more commonly seen in a quiescent microenvironment. Analysis of a combined ISG marker profile by digital pathology stratifies CRC patients into diametrically opposed immune phenotypes. Targeted inhibition of miRNAs within the tumor microenvironment may form a new strategy to stimulate the anti-tumoral immune response.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Immunology and Allergy
Life Sciences > Immunology
Health Sciences > Oncology
Language:English
Date:2017
Deposited On:26 Sep 2019 13:44
Last Modified:28 Jul 2020 14:13
Publisher:Taylor & Francis
ISSN:2162-4011
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1080/2162402x.2017.1288330
PubMed ID:28507795

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