Researchers at UT Southwestern Medical Center have made a significant discovery that could potentially revolutionize cancer treatment, particularly in melanoma and other cancers. Their groundbreaking findings, published in the Journal of Experimental Medicine, highlight a genetic mutation that has the ability to slow down the growth of melanoma tumors and possibly other types of cancer. This discovery holds promise for developing new treatments that could enhance the effectiveness of current cancer immunotherapies, leading to better patient outcomes.
The key breakthrough centers around a genetic mutation that, when present, can harness the power of the immune system to combat cancer. According to Dr. Hexin Shi, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and Immunology at UT Southwestern, this mutation opens the door to a novel therapeutic target. If further developed, this could lead to treatments capable of suppressing a wide variety of cancers, providing new hope for patients who have limited options with current therapies.
Dr. Shi, who co-led the study alongside Dr. Bruce Beutler, M.D., Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine, emphasized the groundbreaking nature of their findings. Dr. Beutler, a recipient of the Nobel Prize in Physiology or Medicine in 2011 for his discovery of a family of receptors that allow mammals to quickly sense infection and initiate an inflammatory response, is also a member of the Cellular Networks in Cancer Research Program at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.
The researchers’ work is especially important because they have identified a genetic mutation that could play a key role in cancer resistance. While scientists have known for some time that mutations in certain genes, called oncogenes, can drive the development of cancer, the idea that there could be genetic mutations that protect against cancer has remained largely speculative. Dr. Shi explained that finding these protective mutations in humans has been challenging because people with these mutations don’t typically exhibit any obvious physical differences from others, making them difficult to study directly in humans.
In their search for potential cancer-protective genes, Dr. Shi, Dr. Beutler, and their colleagues at UT Southwestern used an innovative approach involving genetically engineered mouse models. These mice were created with various genetic mutations, and the researchers observed which mice were resistant to tumor growth or had significantly slower-growing tumors. By using a novel technique called automated meiotic mapping (AMM), developed in Dr. Beutler’s lab, the researchers were able to trace unusual features in these mutant mice to specific genetic mutations responsible for the resistance to cancer.
Through this method, the team quickly identified a gene called H2-Aa as a critical player in the suppression of melanoma and potentially other cancers. H2-Aa is responsible for producing part of a protein called MHC class II, which is essential for the immune system’s ability to distinguish self-proteins from non-self-proteins, triggering an immune response against foreign invaders such as cancer cells. Mice that carried two mutated copies of the H2-Aa gene, causing them to completely lack the H2-Aa protein, exhibited no tumor growth after being exposed to melanoma cells. Furthermore, mice with one mutated copy of the gene showed significantly reduced tumor growth compared to those with the normal (wild-type) form of the gene.
This discovery was a major step forward in understanding the genetic underpinnings of cancer resistance. The researchers’ next step was to investigate the role of H2-Aa in immune cells, specifically a subclass of immune cells known as dendritic cells. These cells play a vital role in activating the immune system’s response to cancer by presenting foreign antigens to other immune cells, including CD8 T cells, which are critical for killing tumor cells. The team found that eliminating H2-Aa from dendritic cells was enough to mimic the effects of completely lacking the protein throughout the entire body. In other words, the absence of H2-Aa in dendritic cells was sufficient to prevent tumor growth.
When the researchers compared the tumor environments of wild-type mice with those of mice lacking H2-Aa, they found that tumors in the mutant mice were infiltrated with significantly more dendritic cells and tumor-fighting CD8 T cells. Moreover, these tumors had far fewer regulatory T cells, which are known to suppress the immune system’s ability to fight cancer. This imbalance in the tumor environment seemed to enhance the immune system’s ability to target and eliminate cancer cells, pointing to the role of H2-Aa as a key factor in limiting cancer growth.
To explore potential treatments based on this discovery, the researchers developed a monoclonal antibody that could block the effects of H2-Aa. Monoclonal antibodies are proteins that can be engineered to target and neutralize specific proteins in the body. When the researchers delivered the monoclonal antibody to mice with melanoma tumors, they observed a significant anticancer effect. However, the results were even more promising when the monoclonal antibody was combined with a checkpoint inhibitor drug, a type of immunotherapy. Checkpoint inhibitors work by blocking the proteins that cancer cells use to evade immune detection, effectively “releasing the brakes” on the immune system and allowing it to attack the cancer. When combined with the H2-Aa-blocking antibody, the checkpoint inhibitor treatment had a much stronger effect on tumor growth, suggesting that targeting H2-Aa could enhance the effectiveness of existing immunotherapies.
On its own, the monoclonal antibody against H2-Aa had a considerable effect on tumor growth, but its impact was dramatically amplified when paired with checkpoint inhibitors. This combination suggests that a therapeutic strategy targeting H2-Aa could potentially improve the response to cancer immunotherapy in patients who do not currently respond to checkpoint inhibitors alone. According to Dr. Beutler, monoclonal antibodies that target the human form of H2-Aa and other closely related proteins could be developed as a new class of cancer treatments. These antibodies could be used either on their own or as a complementary treatment alongside existing immunotherapies.
One of the most promising aspects of this discovery is its potential to address a significant challenge in the treatment of melanoma and other cancers. While checkpoint inhibitors have revolutionized cancer treatment, they are not effective in all patients. In fact, one-half to two-thirds of melanoma patients do not respond to checkpoint inhibitors, leaving many with limited treatment options. Dr. Beutler noted that if the findings from this study can be translated into clinical practice, they could help expand the pool of patients who benefit from checkpoint inhibitors, making these life-saving therapies effective for a broader range of people.
This discovery marks a new chapter in cancer research, offering a potential new therapeutic avenue for those who have limited options with current immunotherapies. The development of monoclonal antibodies targeting H2-Aa and related proteins could not only provide a more effective treatment for melanoma but also offer a new strategy for treating a variety of cancers. As this research moves forward, the hope is that it will lead to clinical trials and eventually, new treatments that could significantly improve the prognosis for cancer patients worldwide.
Reference: Hexin Shi et al, Suppression of melanoma by mice lacking MHC-II: Mechanisms and implications for cancer immunotherapy, Journal of Experimental Medicine (2024). DOI: 10.1084/jem.20240797