Published: 15 February 2017
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, Serge Y. Fuchs
- Colorectal tumors downregulate interferon receptor IFNAR1
Loss of IFNAR1 promotes generation of immune-privileged niche
IFNAR1 regulates viability of cytotoxic lymphocytes and efficacy of immunotherapies
Pharmacologic stabilization of IFNAR1 suppresses tumor growth
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.