title: Tumour-mediated TRAIL-Receptor expression indicates effective apoptotic depletion of infiltrating CD8+ immune cells in clinical colorectal cancer.
abstract: Expression of apoptosis-related proteins on tumour cells has been shown in several experimental models to be an efficient mechanism for a counterattack against host anti-tumour immune responses in solid tumours. Here we provide a clinical evidence for such a tumour immune escape mechanism by demonstrating tumour to T cell-directed death receptor signalling (TRAIL/TRAIL-Receptor (TRAIL-R)) in colorectal cancer (CRC). In a series of patients with CRC and completed 5-year follow up, we investigated apoptosis and expression levels of apoptosis-related proteins. Gene and protein profiles in the tumours demonstrated intratumoural upregulated gene expression for Fas, Fas-L, TRAIL, TRAIL-R and TNF-alpha (RT-qPCR). Levels of terminaldeoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick-end labelling (TUNEL)-positive events were positively correlated with TRAIL-R1-expression on tumour infiltrating immune cells. Among the immune cells, preferentially CD8+ T cells were found to express TRAIL-R1 while serial immunostaining in the same patient tumours showed abundant apoptotic (TUNEL-positive) immune cells. In conclusion, our results in tumour samples from CRC patients suggest TRAIL-R1-mediated apoptotic depletion of infiltrating immune cells (CD8+) in response to TRAIL expression by the tumour itself. This supports the notion of an efficient escape from tumour immune response and thus evasion from the attack of activated CD8+ T cells. These findings may enhance our understanding of tumour progression in CRC and might be helpful for the development of TRAIL and its death receptor-based therapy.
authors.affiliation: Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Grimm
authors.forename: Mia
authors.initials: M
authors.lastname: Kim
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Burkhard H A
authors.initials: BH
authors.lastname: von Raden
authors.forename: Burkhard
authors.initials: B
authors.lastname: von Rahden
authors.forename: Igor
authors.initials: I
authors.lastname: Tsaur
authors.forename: Eva
authors.initials: E
authors.lastname: Meier
authors.forename: Uwe
authors.initials: U
authors.lastname: Heemann
authors.forename: Christoph-Thomas
authors.initials: CT
authors.lastname: Germer
authors.forename: Martin
authors.initials: M
authors.lastname: Gasser
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Waaga-Gasser
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D053218:Receptors, Death Domain / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D007371:Interferon-gamma