Abstract
Pancreatic cancer is one of the most aggressive human cancers. PD1/PDL1-inhibitors recently showed promising results in different cancers with correlation between PDL1 tumor expression and responses. Expression of programmed cell death receptor ligand 1 (PDL1) has been scarcely studied in pancreatic cancer. In this retrospective study, we analyzed PDL1 mRNA expression in 453 clinical pancreatic cancer samples profiled using DNA microarrays and RNASeq. Compared to normal pancreatic samples, PDL1 expression was upregulated in 19% of cancer samples. Upregulation was not associated with clinicopathological features such as patients' age and sex, pathological type, tumor size, lymph node status, and grade, but was associated with shorter disease-free survival and overall survival in multivariate analyses. Analysis of correlations with biological parameters showed that PDL1 upregulation was associated with some degree of lymphocyte infiltration and signs of anti-tumor T-cell response, but to a lesser extent than what has been reported in breast cancer and GIST. PDL1-up pancreatic cancers displayed profiles of lymphocyte exhaustion, were more enriched in inhibitory molecules and pro-tumor populations (Tregs with upregulation of FOXP3 and IL10, myeloid-derived suppressor cells with upregulation of CD33 and S100A8/A9), and demonstrated a down-modulation of most MHC class I members (HLA-A/B/C, HLA-E/F/G) suggestive of a defect in antigen processing and presentation. In conclusion, our results suggest that PDL1 expression might refine the prediction of metastatic relapse in operated pancreatic cancer, and that PD1/PDL1 inhibitors might reactivate inhibited T-cells to increase the anti-tumor immune response in PDL1-upregulated tumors.
Highlights
Pancreatic ductal adenocarcinoma is a major public health problem worldwide with 260,000 deaths annually [1] and its incidence is rising [2]
We analyzed programmed cell death receptor ligand 1 (PDL1) mRNA expression in 453 clinical pancreatic cancer samples pooled from nine data sets
We searched for correlations between PDL1 mRNA expression assessed as binary variable and available clinicopathological features
Summary
Pancreatic ductal adenocarcinoma is a major public health problem worldwide with 260,000 deaths annually [1] and its incidence is rising [2]. Radical resection of the tumor is the only potentially curative treatment, but at diagnosis less than 20% of patients are eligible for surgery. The inoperability and the poor prognosis are due to late diagnosis, propensity to rapid dissemination to lymph nodes and distant organs (>80% of patients displayed metastases at diagnosis) [3], early recurrences after resection, and poor response to available systemic therapies [4, 5]. The median survival in patients with inoperable or metastatic pancreatic cancer is of 6 months www.impactjournals.com/oncotarget from diagnosis and the long-term survival is null. One strategy is the development of immune checkpoint inhibitors that are changing the current treatment paradigm for cancers
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