Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment

Publication date: 13 February 2017
Source:Cancer Cell, Volume 31, Issue 2
Author(s): Kanstantsin V. Katlinski, Jun Gui, Yuliya V. Katlinskaya, Angelíca Ortiz, Riddhita Chakraborty, Sabyasachi Bhattacharya, Christopher J. Carbone, Daniel P. Beiting, Melanie A. Girondo, Amy R. Peck, Ellen Puré, Priya Chatterji, Anil K. Rustgi, J. Alan Diehl, Constantinos Koumenis, Hallgeir Rui, Serge Y. Fuchs
Refractoriness of solid tumors, including colorectal cancers (CRCs), to immunotherapies is attributed to the immunosuppressive tumor microenvironment that protects malignant cells from cytotoxic T lymphocytes (CTLs). We found that downregulation of the type I interferon receptor chain IFNAR1 occurs in human CRC and mouse models of CRC. Downregulation of IFNAR1 in tumor stroma stimulated CRC development and growth, played a key role in formation of the immune-privileged niche, and predicted poor prognosis in human CRC patients. Genetic stabilization of IFNAR1 improved CTL survival and increased the efficacy of the chimeric antigen receptor T cell transfer and PD-1 inhibition. Likewise, pharmacologic stabilization of IFNAR1 suppressed tumor growth providing the rationale for upregulating IFNAR1 to improve anti-cancer therapies.

Graphical abstract

Teaser

Katlinski et al. show reduced type I interferon receptor chain IFNAR1 in colorectal cancer (CRC) stroma, which is important in forming the immune-privileged niche to support CRC development and growth. Stabilization of IFNAR1 improves cytotoxic T lymphocyte survival and suppresses tumor growth.


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