Abstract LB-225: Imprime PGG modulates the function of monocyte-derived M2 macrophages and dendritic cells to drive T-cell expansion

Abstract

Abstract Imprime PGG is a soluble, yeast β-1,3/1,6 glucan currently in phase 3 clinical trial for the treatment of cancer in conjunction with complement-activating, therapeutic monoclonal antibodies (e.g. cetuximab). Imprime PGG is a pathogen- associated molecular pattern (PAMP) that complexes with endogenous anti-β-glucan antibodies, then binds and primes innate immune cells (including neutrophils and monocytes) to kill antibody-targeted cancer cells via a complement receptor 3-dependent mechanism. The early response to a PAMP requires innate immune effector cells (neutrophils, monocytes, macrophages, dendritic cells) and is a prerequisite for subsequent activation of adaptive immune effector cells. Given that macrophages and dendritic cells are the two key antigen presenting cell types that bridge innate and adaptive immunity, the objective of this study was to evaluate the phenotypic and functional effect of Imprime PGG on human monocyte-derived macrophages and dendritic cells (MoDC). Monocytes enriched from Imprime PGG- or vehicle-treated whole blood were cultured in media containing the appropriate cytokines for differentiation of the different cell types: GM-CSF for M1 macrohages; M-CSF for M2 macrophages; M-CSF plus IL-4 for M2a macrophages; and GM-CSF plus IL-4 for dendritic cells. Although Imprime PGG treatment did not affect the expression of CD206, CD209, CD163, HLA-DR, CD80, and CD86 on M1 macrophages, Imprime PGG treatment of whole blood did elicit a substantial reduction in surface expression of the scavenger receptor CD163 on M2 and M2a macrophages. Further, both M2 and M2a macrophages derived from Imprime PGG-treated whole blood substantially enhanced CD3/CD28-stimulated CD4 T cell proliferation and IFNγ production, whereas those from vehicle-treated whole blood did not. MoDC from Imprime PGG-treated whole blood showed increased surface expression of the maturation and co-stimulatory markers CD80, CD83, CD86 as well as HLA-DR. Furthermore, these MoDC also showed enhanced function in an allogeneic mixed lymphocyte reaction, triggering increased CD4 and CD8 T cell expansion and increased IFNγ production versus MoDC from vehicle treated whole blood. Imprime PGG's ability to enhance M2 mediated T cell proliferation and MoDC maturation was maintained even in the presence of tumor conditioned media. These results demonstrate that Imprime PGG treatment drives a coordinated immune response, modulating the function of M2 macrophages and MoDC, enabling the expansion of CD4 and CD8 T cell effector cells, and driving Th1 polarization. These data thereby suggest the potential of combining Imprime PGG treatment with the modalities that relieve tumor-mediated T cell immunosuppression. Citation Format: Anissa SH Chan, Xiaohong Qiu, Adria Jonas, Takashi Kangas, Nadine R. Ottoson, Nandita Bose. Imprime PGG modulates the function of monocyte-derived M2 macrophages and dendritic cells to drive T-cell expansion. [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 LB-225. doi:10.1158/1538-7445.AM2015-LB-225