Combining immunotherapy with chemotherapy, Dacogen (decitabine) in this case, may help to prevent a recurrence of breast cancer, according to a recent study in an animal model of the disease.
In the study, “Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells,” published in the Journal of Leukocyte Biology, researchers found that chemotherapy alone cannot eliminate dormant tumor cells, which become resistant to additional chemotherapy. But when immunotherapy is used in combination with chemotherapy, the majority of these dormant cells are destroyed and the cancer may fail to reappear.
“Immunotherapy is all about timing, ” Masoud H. Manjili, a researcher with the Department of Microbiology and Immunology at Virginia Commonwealth University School of Medicine, said in a press release. “The best way to apply immunotherapy as cancer prevention is during tumor dormancy to prevent advanced stage disease.”
Researchers found that treating breast cancer mouse models with Dacogen induced the death of nearly all tumor cells. But there was a residual population of tumor cells that survived chemotherapy and became dormant.
By measuring the levels of a protein involved in cell division, called Ki-67, the investigators saw that the dormant cells composed two distinct populations: indolent cells, which had a low proliferation rate assessed by the low levels of the Ki-67 protein; and quiescent cells, those that were not proliferating as seen by the lack of Ki-67 expression.
When the research team, led by Manjili, used a product of the immune system, composed of T-cells and natural killer (NK) T-cells engineered to recognize specific proteins of the tumor cells, it found that some of the dormant cells were susceptible to this immunotherapy.
But this effect was only seen in quiescent cells, and not in indolent cancer cells. The researchers believe that this happens because indolent cancer cells can shut down the expression of proteins that are recognized by the immune system, in a process called immunoediting, while quiescent cells cannot. This renders quiescent cells more susceptible to immunotherapies than indolent cells.
“Immunotherapy has become a paradigm shift in medical treatment of disease. Now, instead of our drugs targeting only diseased cells, we can target the immune system and provoke cells of the immune system to do the job for us,” said E. John Wherry, PhD, deputy editor of the Journal of Leukocyte Biology. “This new study demonstrates the importance of this concept of exploiting the immune system in cancer to target residual disease that our cancer drugs miss.”
Although eliminating these cells with the combination of chemotherapy and immunotherapy significantly extended the survival of advanced breast cancer mice models compared to chemotherapy or immunotherapy alone, the researchers report that eventually all mice died with metastatic tumors in the lungs. This suggests that eliminating both quiescent and indolent cancer cells is critical to prevent the cancer from progressing.
“The challenge is to develop combinatorial therapies … that could induce cell-cycle arrest and establish a quiescent type of tumor dormancy so as to render dormant tumor cells resistant to immunoediting and escape from immunotherapy,” the authors wrote.