The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities

Abstract

Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumours despite the use of multi-agent conventional chemotherapy regimens. Such poor outcomes have fuelled ongoing efforts to exploit the tumour microenvironment (TME) for therapy, but strategies aimed at deconstructing the surrounding desmoplastic stroma and targeting the immunosuppressive pathways have largely failed. In fact, evidence has now shown that the stroma is multi-faceted, which illustrates the complexity of exploring features of the TME as isolated targets. In this Review, we describe ways in which the PDAC microenvironment has been targeted and note the current understanding of the clinical outcomes that have unexpectedly contradicted preclinical observations. We also consider the more sophisticated therapeutic strategies under active investigation — multi-modal treatment approaches and exploitation of biologically integrated targets — which aim to remodel the TME against PDAC. Important research efforts are being made to develop therapeutic strategies targeting the tumour microenvironment in pancreatic adenocarcinoma. The authors of this Review describe the apparent contradiction between preclinical studies and clinical outcomes observed to date, presenting more sophisticated strategies under active investigation. Therapeutic approaches to target stromal desmoplasia, a histopathological hallmark of pancreatic ductal adenocarcinoma, have classically focused on depleting the stromal constituents; results have been generally disappointing, owing to the multi-faceted nature of tumour stroma. Isolated strategies to overcome specific immune targets have also met with limited success, likely owing to the presence of multiple immunoregulatory pathways within the pancreatic ductal adenocarcinoma microenvironment. In recognition of the functional complexity of the tumour microenvironment (TME), combining complementary stromal-targeted and immune-targeted treatment modalities to leverage the changes in the TME offers a more rational treatment approach. Points of biological convergence, such as stromal–immune crosstalk, including glutamine metabolism, focal adhesion kinase and transforming growth factor-β signalling, are promising targets for remodelling the TME into an antitumour milieu.