A groundbreaking study published in Cancer Cell has revealed new insights into a common genetic deletion found in multiple types of cancer. The deletion, known as 9p21, is present in about 15% of human cancers, including melanoma, bladder, mesothelioma, and certain brain cancers. Researchers have long known that this deletion is associated with poor patient outcomes and reduced response to immunotherapies. However, the study has uncovered the mechanism behind this association and suggests potential solutions.
The study found that the 9p21 deletion causes cancer cells to release a compound called methylthioadenosine (MTA), which hampers the immune system’s ability to detect and destroy cancer cells. This explains why patients with the 9p21 deletion do not respond well to immunotherapies, which aim to enhance the body’s immune response to cancer cells. However, the researchers also discovered a newly developed drug that has shown promising results in animal studies. The drug reduces MTA levels, rejuvenates the immune system, and increases the presence of aggressive T cells that can target and destroy tumor cells from within.
The 9p21 deletion is significant because it removes important genes responsible for producing proteins that regulate cell growth and division. Without these genes, cancer cells can multiply uncontrollably and become malignant. Additionally, the deletion eliminates a maintenance gene that produces an enzyme to neutralize the toxic MTA. As a result, cancer cells with the 9p21 deletion gain an enhanced ability to suppress the immune system, evading detection and destruction by immune cells.
Lead author of the study, Dr. Everett Stone, explained that the loss of the MTAP gene, which is almost always lost along with CDKN2A in cancers with the 9p21 deletion, plays a crucial role in promoting cancer growth. The study revealed that the loss of MTAP leads to the release of MTA, inhibiting immune cell activity and preventing them from eradicating malignant cells. This discovery helps explain why patients with melanoma and bladder cancer who have the MTAP loss do not respond well to immunotherapies, which are otherwise effective in these cancers.
Experts not involved in the study have praised its findings and potential implications. Dr. Przemyslaw Twardowski highlighted the importance of understanding resistance mechanisms to immunotherapy and reversing them to benefit a broader range of patients. Dr. Wael Harb stressed that targeting MTA metabolism could open up new treatment options for patients with MTAP-deficient cancers, but further research and clinical trials are necessary to validate these findings and evaluate the safety and efficacy of this approach.
While more research is needed to translate these findings into practical applications and patient benefits, this study provides early but promising evidence that targeting the metabolic state of tumors could enhance the benefits of immunotherapy. It offers hope for improving cancer therapies and expanding treatment options for patients with the 9p21 deletion, who currently have limited treatment options.