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

Kölzer, Viktor; Sokol, Lena; Zahnd, Stefan Patrick; Christe, Lucine; Dawson, Heather; Berger, Martin Dave; Inderbitzin, Daniel; Zlobec, Inti; Lugli, Alessandro (2017). Digital analysis and epigenetic regulation of the signature of rejection in colorectal cancer. Oncoimmunology, 6(4), e1288330. Landes Bioscience 10.1080/2162402X.2017.1288330

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Translational Research Unit

UniBE Contributor:

Kölzer, Viktor; Sokol, Lena; Zahnd, Stefan Patrick; Christe, Lucine; Dawson, Heather; Berger, Martin Dave; Inderbitzin, Daniel; Zlobec, Inti and Lugli, Alessandro

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2162-4011

Publisher:

Landes Bioscience

Language:

English

Submitter:

Inti Zlobec

Date Deposited:

01 Feb 2018 15:49

Last Modified:

01 Feb 2018 15:49

Publisher DOI:

10.1080/2162402X.2017.1288330

PubMed ID:

28507795

Uncontrolled Keywords:

Colorectal cancer digital image analysis digital pathology immunotherapy metastasis microRNA tumor microenvironment

URI:

https://boris.unibe.ch/id/eprint/110622

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