Myeloid cells are critical component of tumor microenvironment. Abnormal differentiation of myeloid cells is now considered a major immunological hallmark of cancer. One of the most prominent changes in the myeloid compartment in cancer is the expansion of pathologically activated relatively immature myeloid cells with the potent ability to suppress immune responses ? myeloid-derived suppressor cells (MDSC). In recent years, MDSC emerged as critically important regulators that suppress anti-cancer immunity and limit the efficacy of cancer immune therapy. Therefore, understanding of the mechanisms regulating MDSC function is of fundamental and translational importance. As only small proportion of monocytes and neutrophils acquire characteristics of MDSC, it remains unclear which specific mechanisms are responsible for such conversion. An abundance of immune suppressive mechanisms detected in MDSC also raised the question, why accumulation of these cells in cancer, does not result in profound global immune suppression of the host. This gap in our knowledge impedes progress toward targeting MDSC function in order to increase the efficacy of immunotherapies. Our new preliminary data suggest that type 1 interferons (IFN1) signaling have an intrinsic regulatory role in preventing acquisition of the immune suppressive potential by neutrophils and monocytes and in limiting suppressive activity of MDSC. All IFN1 (including IFN-? and IFN-?) signal via binding to a surface receptor composed of two chains (IFNAR1/2). Based on our preliminary data we hypothesize that IFN1 produced during inflammation or cancer interferes with acquisition of immune suppressive activity by MDSC. During acute viral and bacterial infections this mechanism prevents the development of immune suppressive activity by neutrophils and monocytes, which otherwise would compromise immune responses. In cancer, however, this mechanism is limited due to tumor-induced downregulation of IFNAR1. As a result, negative IFN1 signaling in MDSC is blocked and these cells can display potent suppressive activity that limits the effect of cancer immunotherapy. Thus, targeting down-regulation of IFNAR1 in MDSC may have valuable therapeutic effect. Overall goal of this proposal is to identify biological and biochemical mechanisms negatively regulating immune suppressive activity of MDSC and to develop methods of their therapeutic regulation.

Public Health Relevance

Tumors produce factors that convert normal myeloid cells into myeloid derived suppressor cells (MDSC), which inhibit immune resistance against growing tumor and stimulate tumor growth and progression. Interfering with suppressive activity of MDSC can greatly increase the efficacy of anti-cancer immunotherapeutics. Pilot studies reveal an important role of cytokines of type I interferons family (IFN1) in limiting MDSC activity and point to downregulation of IFN1 receptor as an important mechanism of MDSC- elicited immune suppression. This proposal will delineate the mechanisms of IFN1-dependent MDCS regulation and determine the importance of stabilization of IFN1 receptor for controlling immune suppression and tumor growth.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Kuo, Lillian S
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Wistar Institute
United States
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Tcyganov, Evgenii; Mastio, Jerome; Chen, Eric et al. (2018) Plasticity of myeloid-derived suppressor cells in cancer. Curr Opin Immunol 51:76-82
Zhao, Bin; Bhattacharya, Sabyasachi; Yu, Qiujing et al. (2018) Expression of the IFNAR1 chain of type 1 interferon receptor in benign cells protects against progression of acute leukemia. Leuk Lymphoma 59:171-177