
Researchers at Stanford University have identified a protein, known as ENPP1 that can act as an on/off switch controlling breast cancer cell’s ability to metastasize and resist immunotherapy.
Despite the strides made in cancer immunotherapies, a significant hurdle remains: more than 80 percent of advanced breast cancers resist these promising treatments. Additionally, those patients lucky enough to experience a response often develop metastases, leading to therapy failure in the long run.
Reporting in the Proceedings of the National Academy of Sciences, investigators showed that the ENPP1 enzyme, present in both cancer cells and the healthy tissue surrounding tumors, acts as a regulatory switch, influencing breast cancer’s response to immunotherapy.
High levels of the enzyme were linked to worse immunotherapy outcomes, revealing the protein as a therapeutic target as well as an indicator of immunotherapy success. Lead author and associate professor of biochemistry at Stanford University Lingyin Li optimistically stated: “Our study should offer hope for everyone.”
The researchers explained that immunotherapies such as the monoclonal antibody pembrolizumab, commercially known as Keytruda, work by blocking an immune-dampening interaction between cancer cells and adaptive immune cells known as T cells. However, in order for the therapy to be effective, the tumor must be infiltrated by T cells in the first place—also known as a “hot” tumor. Tumors missing this infiltration, conversely called “cold” tumors are unable to respond to immunotherapy.
A molecule released by cancer cells, called cGAMP can activate T cell infiltration, making the tumor hot. However, lead author Li previously discovered that before it can cause this response, the molecule often becomes degraded by the ENPP1 enzyme, stopping immune infiltration and leaving the cancer unaffected by immunotherapies. This prompted Li to uncover the clinical significance of EPPN1.
Collaborating with the University of San Francisco, Li delved into data from the I-SPY 2 Trial, a groundbreaking breast cancer trial. Analyzing ENPP1 levels at the time of diagnosis, the team found a correlation. Patients with high ENPP1 levels displayed a low response to pembrolizumab and faced an elevated risk of metastases. Conversely, those with low ENPP1 levels exhibited a high response to immunotherapy and experienced no metastases. According to the researchers, ENPP1 emerged as a predictive indicator, foretelling both the response to immunotherapy and the likelihood of relapse.
To further understand the clinical significance of ENPP1’s actions, the team conducted a series of mouse studies, revealing that when ENPP1 was entirely removed or only its cGAMP-chewing ability was eliminated, the outcome remained consistent—reduced tumor growth and decreased metastases. The mechanism at play involved the suppression of a pathway initiated by cGAMP, revealing an on/off switch controlled by ENPP1.
“In essence, ENPP1 acts like a big dam at the top of the waterfall,” explained Li.
The researchers believe that the identification of ENPP1 as a critical player in breast cancer metastasis opens new avenues for clinicians. ENPP1 levels can serve as a valuable tool for determining appropriate treatments, and drugs targeting ENPP1 could potentially enhance the effectiveness of existing therapies. Importantly, several ENPP1 inhibitors are already in clinical development, paving the way for translating these research findings into tangible clinical applications.
While the focus of this study was on breast cancer, Li believes that ENPP1 may play a pivotal role in other “cold” tumors, such as those found in lung cancer, glioblastoma, and pancreatic cancer. The hope is that this groundbreaking research will inspire further investigations into ENPP1’s role across various cancer types, bringing us one step closer to unlocking the secrets of metastasis and improving outcomes for cancer patients worldwide.