Abstract
Overcoming the profound immunosuppression in patients with solid cancers has impeded efficacious immunotherapy. Signal transducers and activators of transcription 3 (STAT3) has recently emerged as a potential target for effective immunotherapy, and in this study, we describe a novel small molecule inhibitor of STAT3 that can penetrate the central nervous system (CNS) in mice and in physiologically relevant doses in vitro and reverse tolerance in immune cells isolated from glioblastoma multiforme (GBM) patients. Specifically, it induces the expression of costimulatory molecules on peripheral macrophages and tumor-infiltrating microglia, stimulates the production of the immune-stimulatory cytokines interleukin 2 (IL-2), IL-4, IL-12, and IL-15, and induces proliferation of effector T cells from GBM patients that are refractory to CD3 stimulation. We show that the functional enhancement of immune responses after STAT3 inhibition is accompanied by up-regulation of several key intracellular signaling molecules that critically regulate T-cell and monocyte activation. Specifically, the phosphorylation of Syk (Tyr352) in monocytes and ZAP-70 (Tyr319) in T cells are enhanced by the STAT-3 inhibitor in marked contrast to toll-like receptor and T-cell receptor agonists, respectively. This novel small molecule STAT3 inhibitor has tremendous potential for clinical applications with its penetration into the CNS, easy parental administration, direct tumor cytotoxicity, and potent immune adjuvant responses in immunosuppressed cancer patients.
Highlights
In patients with solid tumors, systemic immune responses are unable to overcome the immunosuppressive tumor microenvironment [1]
We investigated whether a pharmacologic derivative of the natural compound, caffeic acid (WP1066; Fig. 1A), a small molecule inhibitor of Signal transducers and activators of transcription 3 (STAT3) activity could overcome these immunosuppressive factors
10 mg/kg achieved plasma concentrations in excess of 1 Amol/L, central nervous system (CNS) concentrations in excess of 62 Ag/g (0.1854 Amol/L) of tissue and in U87-MG malignant glioma-bearing animals, and concentrations of 362 Ag/g (1.07 Amol/L) of tumor. These data show that WP1066 can effectively cross the blood-brain barrier and achieve CNS concentrations, a critical factor when determining therapies for glioma patients (Fig. 1B)
Summary
In patients with solid tumors, systemic immune responses are unable to overcome the immunosuppressive tumor microenvironment [1]. We determined that this STAT3 inhibitor could act as a potent immune adjuvant by up-regulating costimulatory molecules CD80 and CD86 in peripheral blood monocytes and glioma-infiltrating microglia/macrophages and induce effector T cell–stimulating cytokines. This STAT3 inhibitor is able to activate and induce proliferation of effector T cells from GBM patients that are refractory to CD3 stimulation.
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