ICOSL Reverse Signaling Orchestrates Macrophage Programming in Pancreatic Adenocarcinoma

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy due to therapeutic inefficacy. While the era of immunotherapy has brought new hope for cancer patients regarding treatment, checkpoint-based immunotherapy has been ineffective partly due to tumor associated macrophages (TAMs) undermining T cell function. Thus, therapies that directly alter macrophage polarization may be an innovative approach to immune-based therapy. Inducible T-cell co-stimulator ligand (ICOSL) is a B7-family co-stimulatory ligand expressed on macrophages. Emerging data shows that ‘reverse signaling’ via co-stimulatory ligands can modulate macrophage function in wound healing and sepsis. However, the consequences of reverse signaling in TAMs in pancreatic cancer are not understood. Our preliminary data demonstrate that ICOSL-/- mice have more aggressive tumors compared with WT mice. ICOSL stimulation resulted in MHCIIhighTNFα + IFNγ + immunogenic macrophage differentiation, which promotes improved T cell function. Based on these data, we hypothesize that ICOSL reverse signaling is integral to TAM activation and promotes T cell anti-tumor immunity. Using syngeneic mouse models of pancreatic cancer, we will determine: 1) whether ICOSL activation in macrophages promotes immunogenic T cell differentiation and 2) if targeting ICOSL in-vivo can have therapeutic potential in PDAC. We suspect that ICOSL is a promising novel target for immunotherapy beyond current T-cell based modalities, ultimately improving treatment options for various human cancers.