Abstract LB-228: Imprime PGG treatment elicits a coordinated antitumor immune response that triggers enhanced expression of PD-L1 on tumor cells as well as monocyte-derived macrophages and dendritic cells
Authors: Nandita Bose, Anissa SH Chan, Adria Jonas, Xiaohong Qiu, Nadine R. Ottoson, Takashi Kangas, Jeremy R. Graff
Journal: Cancer Research (2015)

Abstract Immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1 antibodies are emerging as an important therapeutic modality in NSCLC as well as other cancers, as these therapies block the tumor-induced T cell suppression. Translational studies from clinical trials with PD-1 and PD-L1 targeted therapies have demonstrated that patients whose cancers show PD-L1 on the surface of tumor cells and infiltrating immune cells, or PD-1 on T cells (i.e. “adaptive immune resistance”) derived greatest benefit from these therapies. It has therefore been suggested that the efficacy of these anti-PD-1/PD-L1 immunotherapies could be enhanced by combinations with agents that can adaptively induce PD-L1 expression as a consequence of de novo immune responses within the tumor microenvironment. Here we show that Imprime PGG, a yeast β-1,3/1,6 glucan currently in phase 3 development in combination with complement-activating monoclonal antibodies (e.g. cetuximab), can elicit a coordinated, anti-cancer immune response that prompts a tumor response akin to adaptive immune resistance. Monocytes derived from human whole blood treated with Imprime PGG or vehicle were cultured in media with the appropriate cytokines to foster differentiation of M2 macrophages (M-CSF), M2a macrophages (M-CSF plus IL-4) or dendritic cells (GM-CSF plus IL-4). At the end of differentiation, both M2 and M2a macrophages showed lower surface expression of the scavenger receptor CD163 and elevated levels of surface PD-L1. Imprime PGG treatment also enhanced the ability of both M2 and M2a macrophages to augment CD3/ CD28-stimulated expansion of effector T cells and increased production of IFNγ. Imprime PGG similarly affected monocyte-derived dendritic cells (MoDC), eliciting increased surface expression of the maturation and antigen presentation markers CD80, CD83, CD86, HLA-DR and PD-L1. Furthermore, the MoDC increased CD4 and CD8 T cell proliferation and IFNγ production in an allogeneic mixed lymphocyte reaction. After confirming the ability of Imprime PGG to drive Th1 polarizing immunity, the supernatants from the M2/Mo-DC and T cell co-cultures were incubated with cell lines from numerous cancer types, including NSCLC, breast, pancreatic, colon, and B cell lymphoma. PD-L1 expression was substantially upregulated on A549 (NSCLC), MiaPaCa2 (pancreatic), and SKBR3 (breast) cancer cell lines but not on the colon cancer cell line (HT-29). These results demonstrate that Imprime PGG has the potential to drive PD-L1-upregulating adaptive immune responses by modulating the function of M2 macrophages and MoDC and suggest that further studies to evaluate potential combinatorial approaches of Imprime PGG with immune checkpoint inhibitors are warranted. Citation Format: Nandita Bose, Anissa SH Chan, Adria Jonas, Xiaohong Qiu, Nadine R. Ottoson, Takashi Kangas, Jeremy R. Graff. Imprime PGG treatment elicits a coordinated antitumor immune response that triggers enhanced expression of PD-L1 on tumor cells as well as monocyte-derived macrophages and dendritic cells. [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-228. doi:10.1158/1538-7445.AM2015-LB-228