Abstract
It is estimated that pancreatic cancer will be the second leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options for this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are not completely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, relatively poorer antigenicity compared to other solid tumors, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological, would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.
Highlights
Pancreatic cancer currently has the lowest survival rate of all cancers
Activated Pancreatic stellate cells (PSC) are reported to form a barrier that prevents CD3+ T cells from infiltrating the pancreatic cancer tissue, they stimulate T cell apoptosis, decrease IL2, and decrease IFN7 Th1 secretion, while increasing immune suppressive IL4, IL5 Th2 cytokine secretion [42]. These findings suggest that galectin-1 expression on PSCs plays a crucial role in T-cell response and immunosuppression within the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME), and are consistent with clinical correlative studies that demonstrated that in PDAC the presence of tumor-infiltrating lymphocytes with a high Th2:Th1 cell ratio is associated with worse prognosis [43]
These findings provide a glimmer of hope that other novel immunotherapies, perhaps in combination with different treatment modalities, may be able to overcome resistant mechanisms to immune response in PDAC
Summary
Pancreatic cancer currently has the lowest survival rate of all cancers. Only 8 out of every 100 patients diagnosed with pancreatic cancer survives beyond 5 years [1]. Cluster 4 exhibited reduced levels of all immune and stromal markers with a “mature” or dense collagenous stromal compartment, high stromal volume, low neo-antigen levels and the presence of a KRAS mutation but lack of other canonical genetic events such as CDKN2A, MYC and TP53, which were underrepresented in cluster 4. In both uni- and multi-variate analysis, considering tumor grade and lymph node status, cluster 4 was associated with significantly better overall survival. These epigenetic marks are being incorporated into early phase clinical trials (NCT02929498, NCT02395601 and NCT03009344)
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