Highlights in this article
Despite the success of immunotherapy in melanoma and other cancers, resistance to immunotherapy is frequently observed in cancer patients and effective treatment strategies to overcome resistance to cancer immunotherapy are lacking. In this research, Dr. Jenkins’s research group at Harvard found an effective strategy to overcome current immunotherapy resistance in melanoma using mouse models and patient-derived tumor models. Clinical trials using this strategy will be expected and promising.
Background
Immunotherapy is a type of cancer treatment that helps the immune system fight cancer. It is a form of treatment that uses substances to stimulate or suppress the immune system to help the body fight cancer, infections, and other diseases. There are several different types of immunotherapy, including monoclonal antibody therapy, cancer vaccines, and immune checkpoint inhibitors. These treatments can be used alone or in combination with other cancer therapies, such as chemotherapy, radiation therapy, or surgery. In the clinic, immunotherapy is often used to treat cancers that have not responded to other treatments, or to help reduce the risk of cancer recurrence after other treatments have been completed. It is a promising area of research and is being actively studied in clinical trials for the treatment of a wide range of cancers.
While immunotherapy has shown promising results in treating various types of cancer, some patients do not respond to these treatments or may develop resistance over time. There are several potential mechanisms of resistance to immunotherapy, including tumor-intrinsic factors, immune-intrinsic factors, acquired resistance and Patient factors. Thus, researchers are actively studying the mechanisms of resistance to immunotherapy in order to develop new strategies to overcome it. This includes developing combination therapies that target multiple pathways involved in immune evasion, as well as developing personalized treatment approaches based on individual patient characteristics.
Discovery
Scientists are investigating new targets to enhance the effectiveness of cancer immunotherapy as immunotherapy is not completely successful as described above. Dr. Jenkins laboratory used a novel screening system called CRISPR–Cas9 genome editing, and identified several potential targets to boost the immune system’s attack on cancer cells. However, the translation of these findings into clinical applications remains limited. Dr. Jenkins found that one promising target TANK-binding kinase 1 (TBK1), a protein that coordinates the immune response to invading pathogens. While TBK1 has been identified as a potential immune-evasion gene, disrupting its signaling has also shown early promise in enhancing the response to immunotherapy in mice. They found that genetic deletion of TBK1 sensitizes tumors to immune attack and that pharmacological inhibition of TBK1 can overcome resistance to PD-1 blockade (one of the immunotherapies) in both mice and patient-derived tumor models. Targeting TBK1 lowered the cytotoxicity threshold after exposure to immune-cell-derived effector cytokines, thus making immunotherapy resistant tumors more sensitive to immunotherapy. These findings strongly suggest that TBK1 could be a promising target for improving the effectiveness of cancer immunotherapy. Furthermore, clinical trials examining targeting TBK1 will provide the potential utilization of this strategy.
For more information:
Nature 2023 1/12
https://www.nature.com/articles/s41586-023-05704-6
Targeting TBK1 to overcome resistance to cancer immunotherapy
Dr. Jenkins’s website: