Abstract
According to the cancer stem cells (CSCs) theory, malignant tumors may be heterogeneous in which a small population of CSCs drive the progression of cancer. Because of their intrinsic abilities, CSCs may survive a variety of treatments and then lead to therapeutic resistance and cancer recurrence. Pancreatic CSCs have been reported to be responsible for the malignant behaviors of pancreatic cancer, including suppression of immune protection. Thus, development of immune strategies to eradicate pancreatic CSCs may be of great value for the treatment of pancreatic cancer. In this study, we enriched pancreatic CSCs by culturing Panc-1 cells under sphere-forming conditions. Panc-1 CSCs expressed low levels of HLA-ABC and CD86, as measured by flow cytometry analysis. We further found that the Panc-1 CSCs modulate immunity by inhibiting lymphocyte proliferation which is promoted by phytohemagglutinin (PHA) and anti-CD3 monoclonal antibodies. The monocyte derived dendritic cells (DCs) were charged with total lysates generated from Panc-1 CSCs obtained from tumor sphere culturing. After co-culturing with lymphocytes at different ratios, the Panc-1 CSCs lysates modified DC effectively promoted lymphocyte proliferation. The activating efficiency reached 72.4% and 74.7% at the ratios of 1∶10 and 1∶20 with lymphocytes. The activated lymphocytes secreted high levels of INF-γ and IL-2, which are strong antitumor cytokines. Moreover, Panc-1 CSCs lysates modified DC induced significant cytotoxic effects of lymphocytes on Panc-1 CSCs and parental Panc-1 cells, respectively, as shown by lactate dehydrogenase (LDH) assay. Our study demonstrates that the development of CSCs-based vaccine is a promising strategy for treating pancreatic cancer.
Highlights
Pancreatic cancer is one of the most lethal malignancies of the digestive system, which ranks as the leading cause of cancer-related death in developed countries
The results showed that the proliferation of lymphocyte activated by PHA or anti-CD3 monoclonal antibodies was inhibited in the presence of pancreatic cancer stem cells (CSCs) compared with controls (Fig. 3)
CSCs have been notorious for its resistance to therapy and may be the cause for relapse of malignant tumors, as previously reported [10,11]
Summary
Pancreatic cancer is one of the most lethal malignancies of the digestive system, which ranks as the leading cause of cancer-related death in developed countries. The incidence of pancreatic cancer and the related death is steadily increasing in developing countries, whereas the prognosis of most pancreatic cancer patients did not improve over the last thirty years. The CD44+CD24+ESA+ pancreatic CSCs have been confirmed to possess an increased tumorigenic potential, and are responsible for the malignant behavior of pancreatic cancer [2]. Complete eradicating of these CSCs may provide hope as a novel therapeutic strategy to treat pancreatic cancer. The remnant CSCs may become the origin of recurrence and the source of treatment failure
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