S. W. De Geus1, H. A. Prevoo1, N. G. Dekker-Ensink1, B. A. Bonsing1, H. Morreau2, A. L. Vahrmeijer1, P. J. Van Den Elsen3, C. J. Van De Velde1, P. J. Kuppen1 1Leiden University Medical Center,Surgery,Leiden, 2333 ZA, Netherlands 2Leiden University Medical Center,Pathology,Leiden, 2333 ZA, Netherlands 3Leiden University Medical Center,Immunohematology,Leiden, 2333 ZA, Netherlands
Introduction: Pancreatic cancer has a notoriously dismal prognosis, which is to a large degree caused by its high metastatic potential. Even after complete surgical resection of the primary tumor, distal recurrence rates range from 46% to 89%. Tumor evasion and suppression of the host immune surveillance system has demonstrated to affect clinical outcome in various malignancies. However, the role of immune system in pancreatic cancer remains mainly unclear. The purpose of this study was to investigate the clinical impact of classical human leukocyte antigen (HLA) class I (A, B, C), and non-classical HLA-G and HLA-E tumor expression in pancreatic cancer patients.
Methods: Immunohistochemical stainings were performed for HLA class I (A, B, C), HLA-G and HLA-E tumor expression in pancreatic adenocarcinoma patients (n = 137) who underwent primary surgery between 2003 and 2013. Survival analysis was performed using the multivariate Cox proportional hazard models for overall (OS) and relapse-free (RFS) survival.
Results: HLA class I, HLA-G and HLA-E expression was observed in respectively 50%, 17% and 96% of the pancreatic adenocarcinoma patients. On multivariate analysis, primary tumor stage pT2-4 (HR, 2.188; 95% CI, 1.029-4.653; p=0.042), lymph node stage pN1 (HR, 1.327; 95% CI, 0.809-2.176; p=0.262), and HLA-G expression (HR, 1.743; 95% CI, 1.010-3.009; p=0.046) were associated with unfavorable OS. HLA-G expression resulted in median OS of 10.0 months (95% CI, 3.3 – 16.7 months), whereas absence of HLA-G expression resulted in median OS of 18.0 months (95% CI, 13.9 – 22.1 months). In addition, primary tumor stage pT2-4 (HR, 1.745; 95% CI, 0.851-3.577; p=0.128), lymph node stage pN1 (HR, 1.281; 95% CI, 0.785-2.090; p=0.321), and HLA-G expression (HR, 1.820; 95% Cl, 1.053-3.146; p=0.032) were also independently predictive for adverse RFS. Median RFS was 7.0 months (95% CI, 3.0 – 11.0 months) for patients demonstrating positive HLA-G expression compared to 12.0 months (95% CI, 8.8 – 15.3 months) for patients with absent HLA-G expression. HLA class I and HLA-E expression showed no correlated with OS or RFS in pancreatic adenocarcinoma patients.
Conclusion: This study demonstrated that HLA-G expression was significantly associated with adverse OS and RFS in pancreatic adenocarcinoma patients. Consequently, immunohistochemistry for these markers may aid identification of patients with a poor prognosis, who likely benefit less from an upfront surgical strategy. In addition, these results provide further evidence for the immunogenic character of pancreatic cancer and subsequent potential for therapeutic strategies targeting the immune system.
