Nanocomplexes Drive Immune Cells Against Tumor
Nanoparticles And Immunotherapy of Ovarian Cancer
Aug 4, 2009
Ovarian cancer is the sixth leading cause of cancer-related deaths in the occidental world and the second most common gynecological cancer after breast cancer. It is a leading cause of death from gynecological malignancies accounting for 4% of all cancers among women from industrialized countries. Largely asymptomatic, early detection of ovarian cancer is rare and screening programs in the general population have for the most part been unsuccessful. Over 70% of patients with ovarian cancer are diagnosed at an advanced stage when the disease has already spread in the body.
Nanoparlicles Used in Ovarian Cancer Cells Immunotherapy
A new report offers a promising strategy to force the immune system against cancer cells whose immunotherapy has, so far, not been successful. Using nanoparticles, ultra small beads of polymers, a team of researchers was able to reprogram a protective immune cell that ovarian cancer had modified to its advantage to support the cancer's growth and escape the immune system. In other words, cancer cells reverse the properties of immune cells from being anti-tumor cells to becoming pro-tumor cells. Nanoparticles of polyethylenimine are able to restore immune cells to their normal function of working against cancer.
The new research is published in August 2009 in the Journal of Clinical Investigation, by Dr. Jose Conejo-Garcia and colleagues at Dartmouth-Hitchcock's Norris Cotton Cancer Center (Lebanon, New Hampshire), and is entitled "Polyethylenimine-based siRNA nanocomplexes reprogram tumor associated dendritic cells via the receptor TLR5 to elicit therapeutic antitumor immunity", (Journal of Clinical Investigation, doi 10.1172/JCI37716).
Nanoparticles Target Dendritic Cells Through a Specific Receptor, TLR5
The scientist studied mice with established ovarian tumors, and injected nanoparticles made of polymer of polyethylenimine, now used in clinical trials for other tumors. The polymer interacts with a receptor on dendritic cells, namely TLR5 or Toll-like receptor 5, that senses danger to activate other cells that trigger an inflammatory immune response.
Cancer is more than tumor cells, many other circulating cells including the stromal cells and immune cells such as dendritic phagocytes are involved in cancer development and processus of tumorigenesis. Phagocytes are the soldiers of the immune system that engulf bacteria and other pathogens during a process called phagocytosis. Dendritic cells are particularly abundant in the ovarian cancer environment and were preferentially phagocyting the nanoparticles.
In this report, nanoparticle incorporation was surprisingly able to transform the dendritic cells from an immunosuppressive to an immunostimulatory cell type at the tumor site, provoking an anti-tumor response and also killing tumor cells.
Nanoparticles Wrapped With siRNA are More Efficient Against Cancer Cells
When the researchers used nanoparticles wrapped with a specific small molecule of RNA, namely siRNA, the anti-tumor effect was particularly efficient. The siRNA was specifically targeting another molecule involved in the immune response and known as PD-L1. PD-L1 targets the receptor PD1 present on tumor and immune cells. Addition of this specific siRNA on nanoparticles provokes an increase in the tumor killing and siRNA extends the survival time of mice bearing ovarian cancer.
Ovarian cancer would be a very accessible disease for nanoparticle delivery. Instead of systemic administration, nanocomplexes can be put directly into the peritoneal cavity where the phagocytes are most present. In addition, for ovarian cancer, peritoneal chemotherapy is usually more efficient than standard intravenous chemotherapy. These findings could complement the standard chemotherapeutic treatment because they also target immune cells present around the tumor and not only the cancer cells.
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