The Journal of Immunology, 2007, 178: 50.3.
Copyright © 2007 by The American Association of Immunologists, Inc.
Cooperative downregulation of IFN[gamma]R and Fas is functionally linked to CTL-mediated immunoselection and tumor promotion
Dafeng Yang1,
Kimberly K Smith2,
David Georgi2,
Scott I Abrams3 and
Kebin Liu1
1 Department of Biochemistry and Molecular Biology,
2 Department of Pathology, Medical College of Georgia, 1459 Laney Walker Blvd, Augusta, GA, 30912,
3 Laboratory of Tumor Immunology and Biology, NCI/NIH, 10 Center Drive, Bethesda, MD, 20892
Abstract
The host immune system functions as an intrinsic surveillance network in the recognition and destruction of tumor cells. But the immune system, at the same time can "edit" tumor cells and select for tumor variants with reduced immunogenicity through immunoselection. We report here that Fas and IFN
R were coordinately downregulated in the tumor escape variants in vitro. Examination of spontaneously arising mouse primary mammary carcinoma and lung metastases revealed that both Fas and IFNR protein levels were also dramatically lower in lung metastases than in primary tumors in vivo. Functional disruption of either the Fas-mediated apoptosis pathway, the IFN signaling pathway, or both pathways together enhanced the metastatic capability of tumor cells. Gene expression profiling revealed that altered expression of genes involved in immediate IFNR signaling, the interferon primary response, apoptosis, and tumor colonization are associated with tumor escape. Furthermore, disruption of IFNR function did not alter tumor cell susceptibility to CTL-mediated cytotoxicity, but is linked to enhanced infiltration of endogenous T cells in the tumor microenvironment and tumor promotion in vivo. These findings suggest that coordinate downregulation of Fas and IFNR by tumor cells, two key components of cancer immunosurveillance and immunoediting, leads to a more aggressive metastatic phenotype.
