Biochemical and Biophysical Research Communications
NK cell and IFN signatures are positive prognostic biomarkers for resectable pancreatic cancer
Graphical abstract
Introduction
The outlook for pancreatic cancer patients after surgery remains highly unsatisfactory; approximately 23,000 Japanese die of this disease per year, making it the 4th leading cause of cancer-related deaths in the country. Recent studies have documented that adjuvant chemotherapy using gemcitabine (GEM) or S-1 can improve recurrence-free and overall survival [[1], [2], [3]]. However, the recurrence rate is >80% even after potentially curative surgery. Therefore, development of more effective therapies is urgently needed.
Recently, immune checkpoint inhibitors have shown major clinical benefit, especially in melanoma and lung cancer. However, pancreatic cancer remains poorly responsive to checkpoint blockade [4]. Marked infiltration of immunosuppressive cells into the dense desmoplastic tumor stroma is observed in most pancreatic cancer patients, and intratumoral infiltration of effector cells is commonly very poor. It has been shown that prognosis is better for resectable pancreatic cancer patients whose tumors have more T-cell infiltration. However, the immunological profile and determinants of immune activation in pancreatic cancers are still poorly understood. Novel immunotherapeutic approaches could emerge from a better understanding of these issues.
Here, we performed integrative immunomonitoring of peripheral blood and tumor from resectable pancreatic cancer patients. We sought immunological factors for predicting the prognosis after surgery, which might reveal novel potential targets for pancreatic cancer immunotherapy.
Section snippets
Patient selection
From August 2012 to December 2013, 45 patients with pancreatic cancers underwent surgical resections at the Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery at the University of Tokyo Hospital. Of these, patients with R0 or R1 resections were selected. Patients who were receiving systemic steroid therapy which affects host immune system were excluded. Double cancer cases were also excluded from the study.
Sample preparation, RNA sequencing and data processing
Pancreatic tumors and peripheral blood from the same patients were
Patients
A total of 19 consenting pancreatic cancer patients who received surgery (R0/R1 resections) were analyzed in this study. The patients were 14 males and 5 females, with a median age of 70 years (range, 44–80 years) (Table 1). Pancreaticoduodenectomy was performed in 9 patients, distal pancreatectomy in 9, and total pancreatectomy in the remaining patient. As postoperative adjuvant therapy, 3 patients received GEM alone and 6 a combination of GEM plus γδ T cells in a phase I clinical trial at our
Discussion
In the present study, we performed flow cytometry for the relative quantification of different subsets of immune cells and multiplex bead assays for plasma cytokines and chemokines in the peripheral blood of patients with resectable pancreatic cancer. Furthermore, RNA-Seq gene expression profiling of the tumor was undertaken. By integrating these data into a comprehensive immunomonitoring paradigm, we identified certain immunological features in the periphery and the tumor microenvironment as
Financial support
Funding: This study was supported in part by JSPS KAKENHI (Grants-in-Aid for Scientific Research) Grant Numbers 16H04708 (to K.K.) and 16K07162 (to H.M.) and Pancreas Research Foundation of Japan (to T.A.).
Acknowledgements
We thank Mr. Atsushi Kondo and Tamaki Iino (Department of Immunotherapeutics, The University of Tokyo Hospital) for their wonderful technical assistance.
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