title: IFN-γ-driven intratumoral microenvironment exhibits superior prognostic effect compared with an IFN-α-driven microenvironment in patients with colon carcinoma.
abstract: Interferon (IFN)-α and IFN-γ are cytokines with potent immunomodulating and anti-tumor activities. It is unknown which of the two IFNs may be more potent in the regulation of an anti-tumorigenic response in colorectal carcinoma or whether both cytokines cooperate. We, therefore, established human myxovirus resistance protein A and human guanylate-binding protein-1 as markers for the differential detection of IFN-α- and IFN-γ-driven tumor micromilieus, respectively. In vitro studies with different cultures of tumor cells from colorectal carcinoma and stroma cells showed that the expression of myxovirus resistance protein A was exclusively induced by IFN-α, whereas guanylate-binding protein-1 was strongly induced by IFN-γ and only weakly by IFN-α. This expression pattern was used to distinguish cell activation caused by the two cytokines in a clinical cohort of patients with colon carcinoma (n = 378). Patients with primary tumors expressing only guanylate-binding protein-1 exhibited the highest cancer-specific 5-year survival (94.0%, P = 0.006) compared with those expressing both factors (90.3%, P = 0.006), myxovirus resistance protein A alone (83.5%, P = 0.096), or none (72.8%). Our study describes a successful proof-of-principle approach that complex cytokine interaction networks can be dissected in human tissues and demonstrates that an IFN-γ-driven tumor microenvironment exhibits a superior prognostic effect compared with an IFN-α-driven tumor microenvironment in colon carcinoma.
authors.affiliation: Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Grenz
authors.affiliation: Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Naschberger
authors.affiliation: Department of Internal Medicine 5, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Merkel
authors.affiliation: Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Britzen-Laurent
authors.affiliation: Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Schaal
authors.affiliation: Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Konrad
authors.affiliation: Department of Haematology/Oncology, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Aigner
authors.affiliation: Institute of Pathology, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Tilman T
authors.initials: TT
authors.lastname: Rau
authors.affiliation: Institute of Pathology, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Department of Internal Medicine 5, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Roland S
authors.initials: RS
authors.lastname: Croner
authors.affiliation: Department of Internal Medicine 5, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Hohenberger
authors.affiliation: Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Erlangen, Germany. Electronic address: michael.stuerzl@uk-erlangen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Stürzl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003110:Colonic Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D064547:Myxovirus Resistance Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D012189:Retrospective Studies; D015996:Survival Rate; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines; C490287:GBP1 protein, human; C573415:IFNG protein, human; D016898:Interferon-alpha; D064547:Myxovirus Resistance Proteins; D009363:Neoplasm Proteins; D007371:Interferon-gamma; D019204:GTP-Binding Proteins