Lack of interferon-γ receptor results in a microenvironment favorable for intestinal tumorigenesis

Abstract

IFN-γ plays an important role in innate and adaptive immunity. IFN-γ signaling is also involved in tumorigenesis, with both pro- and antitumor activities documented. We here report the characterization of intestinal tumorigenesis in Apc^Min/+ mice that lack IFN-γ receptor. We observed that Ifngr1^−/−Apc^Min/+ mice are shorter-lived than Ifngr1^+/+Apc^Min/+ mice. The tumors in Ifngr1^−/−Apc^Min/+ mice are more likely to progress into invasive adenocarcinomas. Gene expression profiling by RNA sequencing revealed a significant upregulation of genes involved in inflammation and tissue remodeling in tumors of Ifngr1^−/−Apc^Min/+ mice when compared to those in Ifngr1^+/+Apc^Min/+ mice. In particular, five genes encoding matrix metallopeptidases (MMPs) were among the upregulated. On the other hand, genes that promote or maintain intestinal differentiation, such as Cdx2, Cdhr2 and Cdhr5, were downregulated. Tumor-associated macrophages were more abundant and were more favored toward M2 polarization in Ifngr1^−/−Apc^Min/+ mice than in Ifngr1^+/+Apc^Min/+ mice. Furthermore, the Ifngr1 was significantly downregulated in intestinal tumors when compared to mucosa. A similar trend was noted for human colorectal carcinomas. Together, our results indicate that adequate IFN-γ signaling is critical for maintaining a tumor-prohibitive microenvironment.