T-cell migration and infiltration in solid tumors is a critical step for maximizing the efficacy of many cancer immunotherapies. Hyaluronan (HA) is a glycosaminoglycan that accumulates in the extracellular matrix (ECM) of a range of solid tumors, including pancreatic ductal adenocarcinoma (PDA). PEGylated recombinant human hyaluronidase PH20, pegvorhyaluronidase alfa (PEGPH20; PVHA), is a novel, first-in-class biologic that enzymatically degrades HA in the tumor microenvironment (TME) and is in clinical development in combination with chemotherapy for the treatment of HA-accumulating tumors. Previously, in a murine PDA tumor model, we demonstrated that accumulation of HA restricts T-cell infiltration and promotes immunosuppression. In the present study, we hypothesized that degradation of HA by PEGPH20 would increase access of CD8+ T cells to the tumor. To test this hypothesis, Pan02 murine PDA cells were engineered to overexpress hyaluronan synthase 3 (Pan02-HAS3) and were implanted orthotopically into the pancreas. In Pan02-HAS3 tumors, HA accumulation was 53-fold higher (2606 ng/mg) compared with Pan02 parental tumors (50 ng/mg) as determined by HA ELISA. Degradation of HA in Pan02-HAS3 tumors with intravenous PEGPH20 as a single agent inhibited tumor growth by 58% at a dose of 0.0375 mg/kg and 73% at a dose of 1 mg/kg. Flow cytometric analysis of tumor-infiltrating immune cells in PEGPH20-treated tumors demonstrated a significant increase in the numbers of cytotoxic CD8+ tumor-infiltrating lymphocytes and natural killer (NK) cells versus control tumors. However, no changes in CD8+ T-cell proliferation were detected, as measured by Ki67 expression or bromodeoxyuridine (BrdU) incorporation. Degradation of HA in the TME was also associated with an increased frequency of CD103+ dendritic cells and a decreased frequency of immunosuppressive CD206+ tumor-associated macrophages. These data support prior reports that accumulation of HA in the TME restricts T-cell infiltration and promotes immunosuppression, and that PEGPH20 treatment may facilitate access of CD8+ T cells and NK cells into tumors. These findings are consistent with prior studies and support the ongoing clinical evaluation of combining PEGPH20 with immune checkpoint inhibitors to improve antitumor efficacy in HA-accumulating tumors.
Citation Format: Jisook Lee, Trevor Kimbler, Curtis Thompson, Benjamin J. Thompson. Degradation of hyaluronan from the tumor extracellular matrix increases infiltration of CD8+ T cells and natural killer cells in an orthotopic pancreatic tumor model [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 A46.