Abstract 5034: Imprime PGG decreases regulatory T cell suppression and enhances T cell proliferation and differentiation revealing additional mechanisms for its anti-tumor activity

Abstract

Abstract Imprime PGG is a soluble yeast-derived β-glucan immunomodulator being developed for treatment of cancer in combination with anti-tumor antibodies (Abs). Imprime PGG binds to complement receptor (CR)3 on innate immune cells (neutrophils and monocytes), and primes them to exert anti-tumor activity against Ab-targeted, complement opsonized tumor cells. Numerous studies in syngeneic and human xenogeneic tumor models in mice have demonstrated that administration of Imprime PGG in combination with anti-tumor Ab treatment reduces tumor growth and prolongs survival beyond that observed with either agent alone. In clinical trials, Imprime PGG in combination with tumor-targeting Abs has also been associated with improvements in objective tumor response and survival. Imprime PGG's mechanism of action has been extensively studied in the context of the innate immune system. Whether Imprime PGG may also play a role in the modulation of adaptive immune responses and the cross-talk that exists between the innate immune system and T-cell responses was unclear. Recent work has revealed that Imprime PGG is capable of activating not only the innate immune system but also has the potential of inhibiting the polarization of macrophages into the immunosuppressive M2 phenotype. Since considerable cross-talk exists between the innate and adaptive immune cells in the immunosuppressive tumor microenvironment, we investigated whether Imprime PGG may also play a role in direct or indirect modulation of one of the adaptive immunosuppressive cell types, regulatory T cells (Tregs). We demonstrated that plasma from Imprime PGG treated whole blood (WB) was able to decrease the suppressive capability of Tregs on conventional CD4+ T cells. We also determined that plasma from Imprime PGG treated WB was able to enhance the proliferation of both CD4+ and CD8+ T cells in response to CD3/28 beads and to peptide stimulation in vitro. This enhanced proliferation was accompanied by upregulation of the transcription factor Tbet and increased IFN-γ production suggesting Imprime PGG may drive polarization of T cells to a Th1, anti-tumor phenotype. Interestingly, these effects were greatest when Imprime PGG was added to WB and not to isolated plasma, indicating that the effects of Imprime PGG on the T cell compartment are indirect and may involve cross-talk from the innate immune system. These data are the first to show that Imprime PGG may exert anti-tumor activity not only by re-directing the innate immune system against opsonized tumor cells, but also by re-orienting the adaptive immune compartment toward a Th1, anti-tumor phenotype. Citation Format: Steven M. Leonardo, Keith Gorden, Ross Fulton, Lindsay Wurst. Imprime PGG decreases regulatory T cell suppression and enhances T cell proliferation and differentiation revealing additional mechanisms for its anti-tumor activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5034. doi:10.1158/1538-7445.AM2015-5034