The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancer worldwide, with an overall survival (OS) rate, all stages combined, of still <10% at 5 years. For most patients with unresectable or recurrent PDAC, few therapeutic options are available with limited efficacy (median OS ≤ 12 months). Moreover, immune checkpoint inhibitors that have been tested so far in PDAC failed to improve patient survival. This resistance of PDAC to therapies is, in part, related to the dense tumor stroma, which creates a mechanical barrier around the tumor cells and generates high interstitial pressure, preventing appropriate vascularization and thus limiting exposure to treatments. In that PDAC tumoral microenvironment, the inflammatory cell infiltrates are unbalanced toward an immunosuppressive over pro-inflammatory phenotype. Therefore, there is an urgent need to better define the composition of PDAC stroma and key immune players in order to identify new therapeutic targets and strategies. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancer worldwide with an overall survival rate, all stages combined, of still <10% at 5 years. The poor prognosis is attributed to challenges in early detection, a low opportunity for radical resection, limited response to chemotherapy, radiotherapy, and resistance to immune therapy. Moreover, pancreatic tumoral cells are surrounded by an abundant desmoplastic stroma, which is responsible for creating a mechanical barrier, preventing appropriate vascularization and leading to poor immune cell infiltration. Accumulated evidence suggests that PDAC is impaired with multiple “immune defects”, including a lack of high-quality effector cells (CD4, CD8 T cells, dendritic cells), barriers to effector cell infiltration due to that desmoplastic reaction, and a dominance of immune cells such as regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages, resulting in an immunosuppressive tumor microenvironment (TME). Although recent studies have brought new insights into PDAC immune TME, its understanding remains not fully elucidated. Further studies are required for a better understanding of human PDAC immune TME, which might help to develop potent new therapeutic strategies by correcting these immune defects with the hope to unlock the resistance to (immune) therapy. In this review, we describe the main effector immune cells and immunosuppressive actors involved in human PDAC TME, as well as their implications as potential biomarkers and therapeutic targets.