IFN-γ-Driven Intratumoral Microenvironment Exhibits Superior Prognostic Effect Compared with an IFN-α-Driven Microenvironment in Patients with Colon Carcinoma

Interferon (IFN)-alpha and IFN-gamma 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-alpha- and IFN-gamma 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-alpha, whereas guanylate-binding protein-1 was strongly induced by IFN-gamma and only weakly by IFN-alpha. 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-gamma-driven tumor microenvironment exhibits a superior prognostic effect compared with an IFN-alpha-driven tumor microenvironment in colon carcinoma.