New research in 5 human cancer cell lines revealed interdependencies between a tumor and its host’s microenvironment.
Researchers in the cancer nanomedicine community debate whether use of nanoparticles can best deliver drug therapy to tumors passively by adding a targeted anti-cancer molecule to bind to specific cancer cell receptor and, in theory, keep the nanoparticle in the tumor longer.
According to a study published in Science Advances, new research on tumors by investigators at the Johns Hopkins Kimmel Cancer Center suggest that the question is more complicated. Laboratory testing of 5 human cancer cell lines with 3 variants of the immune system found that nanoparticles coated with trastuzumab, a drug that targets human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells, were better retained in the tumors than plain nanoparticles, even in tumors that did not express the pro-growth HER2 protein.
However, immune cells of the host exposed to nanoparticles induced an anti-cancer immune response by activating T cells that invaded and slowed tumor growth.
“It’s been known for a long time that nanoparticles, when injected into the bloodstream, are picked up a scavenger-like macrophages and other immune system cells,” said senior study author Robert Ikov, PhD, MSc. “Many researchers in the field have been focused on trying to reduce interaction with immune cells, because they have been trying to increase the circulation time of the nanoparticles and their retention in tumor cells. But our study demonstrates that the immune cells in the tumor collect and react to the particles in such a way to stimulate an anti-cancer response. This may hold potential for advancing beyond drug delivery toward developing cancer immunotherapies.”
The researchers conducted in vitro experiments by applying some plain starch-coated iron oxide nanoparticles and others coated with trastuzumab to 5 human breast cancer cell lines. They found that the amount of binding between the trastuzumab-coated nanoparticles and cells depended on how much the cancer cells expressed the oncogene HER2. In patients, HER-positive breast cancers are among the most resistant to standard chemotherapy. Trastuzumab (Herceptin, Genentech) targets HER2-postive tumor cells and triggers the immune system as well.
Researchers had previously suspected that animals’ immune systems were interacting strongly with the nanoparticles and playing a role in determining retention of the particles in the tumor, whether or not a drug was added. Experiments revealed that tumor-associated immune cells were responsible for collecting the nanoparticles and that cell lines with an intact immune system retained more of the trastuzumab-coated nanoparticles than those without.
In addition, inflammatory immune cells in the tumors’ immediate surroundings seized more of the coated nanoparticles than the plain ones, according to the study. Finally, in a series of 30-day experiments, the researchers found that exposure to nanoparticles inhibited tumor growth 3 to 5 times more than controls, and increased CD8-positive cancer-killing T cells in the tumors.
The anti-cancer immune activating response was equally effective with exposure to either plain or trastuzumab-coated nanoparticles. The investigators said that this demonstrated that systemic exposure to nanoparticles can cause a systemic host immune response that leads to anti-cancer immune stimulation and does not require nanoparticles to be inside the tumors.
The work suggests that complex interdependencies exist between the host and tumor immune responses to nanoparticle exposure. These results offer possibilities for exploring nanoparticle targeting of the tumor immune microenvironment and demonstrate exciting new potential to develop nanoparticles as platforms for cancer immune therapies, according to the study.
The investigators next plan to study whether the same types of immune responses can be generated for noncancer conditions, such as infectious diseases.