Purpose: Immunotherapy, such as checkpoint inhibitors against anti-programmed death-ligand 1 (PD-L1), has not been successful in treating patients with pancreatic ductal adenocarcinoma (PDAC). Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and the TGF-β cytokine are critical in anti-cancer immunity. We hypothesized that TGF-β enhances the immunosuppressive effects of TAM, MDSC, and DC presence in tumors.
Methods: Using a murine PDAC cell line derived from a genetically engineered mouse model, we orthotopically implanted treated cells plus drug embedded in Matrigel into immunocompetent mice. Treatments included saline control, TGF-β1, or a TGF-β receptor 1 small molecule inhibitor, galunisertib. We investigated TAM, MDSC, DC, and TAM PD-L1 expression with flow cytometry in tumors. Separately, we used the TIMER2.0 database to analyze TAM and PD-L1 gene expression in human PDAC tumors in TCGA database.
Results: TGF-β did not alter MDSC or DC frequencies in the primary tumors. However, in PDAC metastases to the liver, TGF-β decreased the proportion of MDSCs (P=0.022) and DCs (P=0.005). TGF-β significantly increased the percent of high PD-L1 expressing TAMs (32 ± 6 % vs. 12 ± 5%, P=0.013) but not the proportion of TAMs in primary and metastatic tumors. TAM PD-L1 gene expression in TCGA PDAC database was significantly correlated with tgb1 and tgfbr1 gene expression (P<0.01).
Conclusions: TGF-β is important in PDAC anti-tumor immunity, demonstrating context-dependent impact on immune cells. TGF-β has an overall immunosuppressive effect mediated by TAM PD-L1 expression and decreased presence of DCs. Future investigations will focus on enhancing anti-cancer immune effects of TGF-β receptor inhibition.
Keywords: PD-L1; PDAC; Pancreatic cancer; TAMs; TGF-β; Tumor-associated macrophages.
© 2021. The Society for Surgery of the Alimentary Tract.