Intratumoral administration of CHST15 siRNA remodels tumoral stroma and tumor-draining lymph nodes and augments tumor-infiltrating T cells in pancreatic cancer in mice

The dense stroma is one cause of poor efficacy of T cell-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC). Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan-synthetic enzyme responsible for remodeling tumor stroma. Intratumoral injection of CHST15 siRNA has been shown to increase the tumor-infiltrating T cells (TILs) in patients with unresectable PDAC. However, the mechanism underlying the enhanced accumulation of TILs is not fully explored. Here, we demonstrate that intra-tumoral injection of CHST15 siRNA locally and remotely diminishes myeloid-derived suppressor cells (MDSCs) and enhances TILs in mice. CHST15 was expressed by tumor cells and MDSCs in both tumor and tumor-draining lymph node (TDLN), and CHST15 siRNA repressed stromal density, neutrophil extracellular traps, and Ly6C/G+ MDSCs in vivo. Remarkably, tumor growth inhibition was only observed in the immunocompetent KPC model, which is associated with enhanced TILs. In vitro, CHST15 siRNA significantly downregulated the levels of CHST15 and indoleamine 2,3-dioxygenase mRNA in CD33+ MDSCs derived from human PBMCs. These results suggest a dual role for intratumorally injected CHST15 siRNA on modulating tumor immune microenvironment for T cell entry and remotely diminishing CHST15+ MDSCs, reducing T cell suppression and expanding T cells in the TDLN, ultimately leading to an enhanced accumulation of TILs.