Researchers from the University of Pittsburgh have developed a new cancer treatment strategy involving co-delivery of a chemotherapy drug and a newly identified immunotherapy. The team’s mission was to find new ways to eliminate residual cancer cells that evade chemotherapy and radiation. “We took a dual approach to find new therapeutic targets and also improve the efficiency of drug delivery,” explains senior author Song Li, M.D., Ph.D., professor of pharmaceutical sciences in the Pitt School of Pharmacy and UPMC Hillman Cancer Center. Results of their work developing a dual-action nanoparticle are published in a paper in Nature Nanotechnology.
The new immunotherapy approach silences a gene that the researchers discovered was involved in immunosuppression. Their starting point focused on Xkr8, a protein that controls distribution and regulation of phosphatidylserine (PS), a lipid which is normally restricted to inner layer of a tumor cell’s plasma membrane but migrates to the outer surface in response to chemotherapy drugs.
“Under normal circumstances Xkr8 is not active,” said Li. “But when cancer cells are treated with an anticancer drug or radiation, the expression of Xkr8 is significantly induced.” In a cascade of events, once activated, Xkr8 pushes PS to be exposed exposure on the cancer cell’s surface. Consequently, macrophages will engage with PS and cause immunosuppression, protecting remaining cancer cells from the immune system and allowing them to survive and grow.
“We need to block this immunosuppression so the immune system can be activated and take care of the remaining live tumor cells,” says Li. To do so, the team’s strategy involved blocking the induction of Xkr8 during chemo, thereby eliminating PS exposure on cancer cell membranes, and ultimately reversing immunosuppression while simultaneously knocking out cancer cells.
In the past, other researchers have realized the immunosuppressive role of the PS on a cell surface and tried to block it. But they found that the blocking agents may not reach all the tumor cells with exposed PS.
So far, no small-molecule inhibitors of Xkr8 are currently available. Instead, the Pitt team used designed snippets of genetic code called short interference RNA (siRNA), to shut down production of the Xkr8 protein. Next, they tested the effectiveness of co-delivery of a prodrug conjugate of two drugs, 5-FU and oxoplatin (FuOXP), which are two front-line agents in the treatment of colorectal and pancreatic cancer.
Li’s team then packaged the siRNA and FuOXP into dual-action nanoparticles and unleashed them in mouse models of pancreatic and colorectal cancer. They found that the nanoparticles dramatically reduced the migration of immunosuppressing PS to the cell surface compared to nanoparticles containing only FuOXP chemotherapy. The mice receiving the nanoparticles containing both FuOXP and siRNA had better tumor microenvironments with more cancer-fighting T cells and fewer immunosuppressive regulatory T cells than animals that received placebo or just siRNA or FuOXP. More to the point, the siRNA/FuOXP-dosed animals also exhibited decreased tumor size.
“In this study, for the first time we were able to establish Xkr8 as an anti-cancer target,” said Li. “And using siRNA, we achieved the PS externalization blockade and made it exhibit a robust anti-cancer efficacy.”
The team has also studied other cancer drugs like doxorubicin and paclitaxel in cell cultures. Li adds, “We have every reason to believe this dual approach can be extended to other types of solid tumors.”
