Treatment with Imprime PGG, a soluble yeast beta-glucan PAMP, induces trafficking of activated Ly6Ghigh cells to secondary lymphoid organs and tumor and facilitates immune activation within the tumor microenvironment.

Imprime PGG (Imprime), an intravenously administered, soluble, yeast β-1,3/1,6 glucan, is currently in clinical development with tumor-targeting, antiangiogenic and checkpoint inhibitor antibodies. The fundamental mechanistic rationale for these different therapeutic combinations is that Imprime, a pathogen-associated molecular pattern (PAMP), primes innate immune effector functions to drive a coordinated anticancer immune response. Previous preclinical mechanistic work has shown that Imprime activates the functionalities of monocytes, macrophages, and dendritic cells (cells that principally influence the TME), eliciting a tumor microenvironment (TME) that activates T cell-dependent antitumor immunity. Studies have shown that mature neutrophils and immature myeloid-derived suppressor cells (PMN-MDSC) accumulate, like other myeloid cells, in the tumor and play a role in establishing the immunosuppressive TME and impair T-cell immunity. Herein, we provide evidence that Imprime treatment reorients neutrophil function, enlisting these cells in anticancer immunity. To date, exploration of the effect of Imprime on neutrophils has evaluated direct neutrophil-mediated tumor killing. In this study, we further explored the impact of Imprime treatment on mature neutrophils and immature PMN-MDSC (i.e., the Ly6Ghigh population) in both tumor-free and tumor-bearing mice. In tumor-free C57BL/6 mice, Imprime mobilized Ly6Ghigh cells into the blood, spleen, and skin draining lymph nodes (sdLNs). The increase of these cells in the sdLN coincided with increased levels of CCL2, CCL3, CCL4, CXCL1 and CXCL10, chemokines important for the mobilization of myeloid cells. In the H1299 lung cancer xenograft model, the addition of Imprime to bevacizumab enhanced CD86 expression on Ly6Ghigh cells in both spleen and tumor tissues when compared to bevacizumab alone, indicating that these cells could play a role in T-cell activation. We therefore assessed the effect of Imprime in MC-38, syngeneic tumor model, shown to be sensitive to Imprime in combination with immune checkpoint inhibitor antiboides (i.e., anti-PD1 and PD-L1). Consistent with our earlier findings, Imprime and Imprime + anti-PD-1 treatments significantly increased the percentage of Ly6Ghigh cells in the spleen and the tumor compared to the vehicle alone. The Ly6Ghigh cells in both the spleen and TME showed increased expression of CD86, MHCII and PD-L1. The enriched PMN-MDSC (~60-70% Ly6Ghigh) from the spleens of Imprime-treated mice were significantly less suppressive to CD3/CD28-mediated proliferation of CD3+ splenocytes. Collectively, these data show that neutrophils have a role in Imprime-mediated remodeling of the immunosuppressive TME, driving a more conducive environment to T-cell immunity. The effects of Imprime on peripheral and tumor-associated neutrophils in cancer patients are currently being explored in phase 2 clinical trials employing the combination of Imprime and anti-PD1 antibody, pembrolizumab. Citation Format: Adria L. Bykowski Jonas, Anissa S.H. Chan, Nadine C. Ottoson, Xiaohong Qui, Keith Gordon, Mark Uhlik, Jeremy Graff, Nandita Bose. Treatment with Imprime PGG, a soluble yeast β-glucan PAMP, induces trafficking of activated Ly6Ghigh cells to secondary lymphoid organs and tumor and facilitates immune activation within the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A01.