title: The relationships between serum cytokine levels and tumor infiltrating immune cells and their clinical significance in colorectal cancer.
abstract: Increased inflammatory cell infiltration correlates to improved survival in colorectal cancer (CRC). Development and progression of CRC is associated with alterations in serum cytokine levels but their significance is not well defined. In this study, we investigated the relationships between the serum levels of 13 cytokines and the densities of eight types of tumor infiltrating inflammatory cells and their impact on disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) in a prospectively recruited group of 147 CRC patients. There were strong positive correlations between the serum concentrations of different cytokines, as well as between the different types of tumor infiltrating immune cells, whereas the associations between serum cytokines and tumor infiltrating immune cells were generally weak. High serum IL-12 levels associated with increased densities of peritumoral CD8(+) T cells, intraepithelial CD3(+) T cells and intratumoral neutrophils, while high serum CCL4 levels associated with increased densities of peritumoral CD68(+) cells. In multivariate survival models, increased infiltration of intraepithelial CD3(+) T cells and increased serum CCL4 associated with improved DFS, whereas higher intratumoral CD83(+) dendritic cell density and increased serum interferon gamma levels associated with improved CSS and OS. Also high density of peritumoral CD3(+) T cells associated with improved CSS. In conclusion, serum cytokines and tumor infiltrating immune cells in CRC represent entities with high intragroup correlations but relatively weak intergroup correlations. The results suggest that tumor infiltrating CD3(+) T cells, CD83(+) dendritic cells, serum CCL4 and serum interferon gamma represent relevant markers of disease outcome.
authors.affiliation: Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.|Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Juha P
authors.initials: JP
authors.lastname: Väyrynen
authors.affiliation: Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.|Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Kantola
authors.affiliation: Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.|Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Väyrynen
authors.affiliation: Department of Surgery, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.|Research Unit of Surgery, Anesthesia and Intensive Care, University of Oulu, Oulu, Finland.
authors.forename: Kai
authors.initials: K
authors.lastname: Klintrup
authors.affiliation: Medical Informatics Group, University of Oulu, Oulu, Finland.
authors.forename: Risto
authors.initials: R
authors.lastname: Bloigu
authors.affiliation: Research Unit of Biomedicine, University of Oulu, Oulu, Finland.
authors.forename: Toni
authors.initials: T
authors.lastname: Karhu
authors.affiliation: Department of Surgery, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.|Research Unit of Surgery, Anesthesia and Intensive Care, University of Oulu, Oulu, Finland.
authors.forename: Jyrki
authors.initials: J
authors.lastname: Mäkelä
authors.affiliation: Research Unit of Biomedicine, University of Oulu, Oulu, Finland.|Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Herzig
authors.affiliation: Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.|Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Tuomo J
authors.initials: TJ
authors.lastname: Karttunen
authors.affiliation: Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.|Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Tuomisto
authors.affiliation: Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.|Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Mäkinen
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D054407:Chemokine CCL4 / Q000097:blood*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood*; D018664:Interleukin-12 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000473:pathology*; D011379:Prognosis
chemical_list: D054407:Chemokine CCL4; D016207:Cytokines; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: T cell; colorectal cancer; cytokine; dendritic cell; serum