Emerging Role for IL-1α Inhibition in Cancer Therapeutics

TNFα is an inflammatory cytokine and anti-TNFα therapy has been used for a variety of ailments. Since IL-1 is upregulated by TNFα signalling, researchers have began to hone in on IL-1’s role to look more specifically at which particular action of TNFα has the most therapeutic promise. This article, IL-1 blockade, discusses the aspects of the research leading up to the discovery of IL-1’s (both IL-1α’s and β’s) role in aiding tumorigenesis and chronic inflammation. It’s often difficult to conduct clinical trials on humans that involve a placebo, especially with cancer patients, due to ethical reasons. When cancer patients are enrolled in clinical trials, the control group always gets chemotherapy and the variable group gets chemotherapy on top of the experimental treatment. Dr. Charles Dinarello used correlative data based on a longitudinal clinical trial for an experimental heart medication, when the researchers followed up the patients at various time points years later. They found that the people who had received the IL-1 inhibitor were over 50% less likely to die from lung cancer than the people in the control group who received a different medication. The age range of the study was in an older population and so Dr. Dinarello suspected that the increase of lung cancer incidence wasn’t due to prevention of tumor initiation, but rather, the participants in the study were in early stages of lung cancer and the group that received IL-1 inhibitors had remission of the cancer without being aware of it (Immunology Conference, 2017). Since this wasn’t an official study on cancer, it didn’t have the same restrictions as it otherwise would have and therefore serves as strong preliminary data to start researching how this could could become a potential therapy for cancer patients. Another study published in Nature found that certain cancers, such as breast cancer, demonstrated a decrease in tumor growth and metastasis when inflammasome activity was decreased. The inflammasome is responsible for converting pro-IL-1β into its mature form after cleavage by caspase-1. Anti-IL-1β therapy has demonstrated promise in Multiple Myeloma and other cancers. Inflammatory stimuli act through TLR and IL-1R signal transduction pathways to upregulate mRNA transcription of the pro-IL-1β as well as the inflammasome. An example of such a stimuli is IL-1α which is released by necrotic cells such as cancer cells that run out of nutrients in their microenvironment. This leads to production of IL-1β in certain cells, but separate from its role in increasing IL-1β production, IL-1α also contributes to induction of chemokines and local inflammation prior to IL-1β’s arrival.  There is ideally a temporally distinct two-step process in inflammatory induction in response to infection or tissue damage. This includes the initial inflammatory response which involves the recruitment of various immune cells as a result of chemokines released by cells that are stimulated with IL-1α. The second step is to heal the “wound” and this is mediated by IL-1β. Based on this model, inhibiting IL-1α may prove to be a more specific therapy in certain cancers since inflammation can lead to angiogenesis, metastasis, and immunosuppression. Current drugs used in anti-IL-1 treatments have a higher specificity for inhibiting IL-1β and so clinical trials are currently being conducted to test the efficacy of monoclonal IL-1α antibodies.