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

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.

Keywords: desmoplastic stroma; immune cells; pancreatic ductal adenocarcinoma; tumoral microenvironment.

Figure 1

Extracellular matrix in pancreatic ductal adenocarcinoma and tumor growth promotion. Abundant stroma is mainly composed of cancer-associated fibroblasts (CAFs) and collagenous proteins leading to hypoxia, immune evasion, and immunotolerant state through recruitment of immunosuppressive cells (MDSCs, Tregs) and suppressive effect on effector immune cells (CD8⁺ T cells, dendritic cells). MDSCs: myeloid-derived suppressor cells; Tregs: regulatory T cells.

Figure 2

Effector immune cells and immunosuppressive cells in human pancreatic cancer. Activated CD8⁺ T cells attack tumor cells presenting tumor-associated antigens peptides on their surface, as dendritic cells. CD4⁺ T cells target tumor cells either directly by eliminating tumor cells through cytolytic mechanisms or indirectly by modulating the TME. Tregs and MDSCs cells play immunosuppressive roles in inhibiting the immune response against PDAC cells by directly inhibiting the anti-tumor functions of T and NK cells. The TAM phenotype is a consequence of the continuous presence of growth factors such as colony-stimulating factor-1 (CSF1) and its receptor (CSF-1R). TAMs release various growth factors and cytokines and promote tumor cell invasion, induce angiogenesis, suppress antitumor immunity, and facilitate tumor cell metastasis. CSF-1R: colony-stimulating factor-1 receptor; MDSC: myeloid-derived suppressor cells; NK: natural killer; TAMs = tumor-associated macrophages; Treg = regulatory T cell.