Recent work has shed light on another way in which tumors escape immune cell recognition. It is well known that cancer secretes proteins, molecules, and other factors that dysregulate antitumor immunity. Once a tumor is established, many immune cells are inhibited or suppressed to act on the rapidly growing cancer. Decades of research have investigated the different ways in which cancer cells prevent immune activation. Current therapies are aimed at several of these mechanisms with limited therapeutic efficacy in single agent strategies. However, a new report suggests that tumors escape therapeutic response in another way.
A recent article in Science Advances, by Dr. Seamus J. Martin and others, demonstrated that cancer cells undergo an inert state that protects them from antitumor cells. Specifically, it was reported that chemotherapy-induced immunity was unable to recognize and target cancer cells that were inert or senescent. Senescence is the biological process of a low-activity cell that does not divide. This state is common in damaged or older cells. This early form of senescence that researchers found in cancer cells is also observed in early wound healing processes.
Martin is the Smurfit Chair of Medical Genetics in the Smurfit Institute of Genetics at Trinity College Dublin. He is world renowned for his work on programmed cell death or apoptosis. He has been awarded numerous prizes for revealing how cells develop and function before enacting an internal elimination process. His current work still investigates different aspects of apoptosis, but focuses on the process within the context of inflammation and cancer.
Wound healing encompasses multiple different cell types that stimulate cell division. This process is accompanied by an increase in oxygen and nutrients to meet the energy levels of the rapidly dividing cells. This highly complex and precise system occurs only during injury, but cancer cells can take advantage of these wound healing mechanisms by acting like damaged cells. Tumor cells were found to appear like they were injured to receive a large source of oxygen and nutrients, which is needed for rapidly dividing cancer. The report further describes the way in which tumors hijack wound healing complexes to promote growth. Unfortunately, it was previously unclear how this process occurred.
Martin and his team discovered that a molecule called Inhibitor of Apoptosis Proteins (IAPs) allows tumors to ‘fly under the radar’. Research suggests that IAPs neutralizes ‘Death Receptors’ that are commonly turned on by chemotherapy drugs and signal to the immune system that cancer cells need to be eliminated. This neutralization stops immune cell recognition from occurring and allows tumors to continue to proliferate. Additionally, IAPs allow for cancer to become senescent, which triggers wound healing processes and helps tumors progress after chemotherapy treatment.
Martin and his team discovered how cancer cells adapt to chemotherapy and maintain development by escaping antitumor immunity. These novel findings improve our understanding of cancer biology as well as chemotherapy mechanisms. As a result, this work has the potential to improve chemotherapeutic treatment strategies. Overall, the report elucidates the mechanism by which cancer cells avoid chemo-induced death and has the opportunity to enhance current standard-of-care therapy.
article, Science Advances, Seamus J. Martin, Smurfit Institute of Genetics, Trinity College Dublin