Bortezomib improves antitumor CD8+ T cell function by modulating miR-155 and its targets

Abstract

Abstract The immunosuppressive tumor microenvironment dampens host antitumor immunity by multiple mechanisms including interfering with various cell signaling pathways that aid in the differentiation and function of immune cells. We have taken an immunotherapeutic approach in order to strengthen antitumor immunity in mice bearing solid tumors, specifically breast tumors. In doing so, we observed that treatment with bortezomib, an FDA-approved proteasome inhibitor, has the ability to increase CD8+T lymphocyte IFNγ secretion and expression of effector molecules, perforin, granzyme-B and the T-box transcription factor eomesodermin. In order to understand the molecular mechanism(s) of how bortezomib works to improve antitumor immunity we sought to explore its effects on miRNA expression as well as function. We found that treatment of wild-type or tumor-bearing BALB/c mice with bortezomib modulated the expression of various miRNAs in CD8+T cells. From miRNA array data, we identified miR-155 as one prominent modulator of antitumor CD8+T cell immune functions. miR-155 has been accredited to controlling CD8+T cell responses by regulating interferon signaling in viral infections and cancer. We are currently elucidating the mechanisms of bortezomib-mediated effects on miR-155 and its targets, such as suppressor of cytokine signaling 1 (SOCS1) and inositol polyphosphate-5-phosphatase (SHIP1) that are associated with T cell function. These data provide novel insights on using bortezomib not only as an agent to sensitize tumors to cell death, but also to provide lymphocyte-stimulatory effects that could overcome immunosuppressive actions of tumor on antitumor T cell function.