Researchers found that chemotherapy alone leads to two types of dormant cancer cells that are not killed outright and become resistant to additional chemotherapy, but when combined with immunotherapy, a majority of dormant cells also is destroyed.
“Immunotherapy is all about timing, ” said Masoud H. Manjili, a researcher involved in the work from the Department of Microbiology and Immunology, VCU School of Medicine, Richmond, Virginia. “The best way to apply immunotherapy as cancer prevention is during tumor dormancy to prevent advanced stage disease.”
To make this discovery, researchers treated breast cancer cells with a common chemotherapeutic agent. Nearly all of the cancer cells died as a result, but a residual population of tumor cells survived and became dormant. By measuring for the presence of a molecule associated with cell division, the scientists determined that this residual population of dormant cancer cells consisted of an indolent as well as a quiescent population. Then, they treated the dormant cells with a product of the immune system, they found that dormant cells were susceptible to immunotherapy, and that quiescent, but not indolent cancer cells, could not escape from immunotherapy.
“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, Ph.D., 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.”
Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells and poor immunogenicity of the tumor-expressing self-antigens. To overcome these barriers, we reprogrammed tumor-immune cell cross-talk by combined use of decitabine and adoptive immunotherapy, containing tumor-sensitized T cells and CD25+ NKT cells. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid-derived suppressor cells and the presence of CD25+ NKT cells rendered T cells, resistant to remaining myeloid-derived suppressor cells. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. Adoptive immunotherapy also induced tumor immunoediting, resulting in tumor escape and associated disease-related mortality. To identify a tumor target that is incapable of escape from the immune response, we used dormant tumor cells. We used Adriamycin chemotherapy or radiation therapy, which simultaneously induce tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of Adriamycin or radiation therapy, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 and quiescent cells that were Ki67 negative. Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that immunotherapy could be highly effective against quiescent dormant tumor cells. The challenge is to develop combinatorial therapies that could establish a quiescent type of tumor dormancy, which would be the best target for immunotherapy.
SOURCES- Eurekalert, Journal of Leukocyte Biology