By Lina carolina 
A groundbreaking discovery, nearly four decades in the making, has revealed that erythropoietin (EPO), a protein primarily recognized for its role in stimulating red blood cell production, possesses a previously unknown and critical function in suppressing the immune system’s ability to combat cancer. This revelation, emerging from research published in the prestigious journal Science, has the potential to revolutionize the treatment of numerous cancers, particularly those notoriously resistant to current immunotherapies.
The study, led by Dr. David Kung-Chun Chiu, a basic life research scientist, and senior author Dr. Edgar Engleman, a professor of pathology and medicine at Stanford University, demonstrated that by blocking EPO’s activity, researchers were able to transform previously immune-resistant "cold" liver tumors in mice into "hot" tumors, teeming with cancer-fighting immune cells. When this blockade was combined with a targeted immunotherapy, the treatment resulted in the complete regression of existing liver tumors in the majority of the experimental animals, with treated mice surviving for the duration of the study. In stark contrast, control groups succumbed to the disease within a few weeks, highlighting the profound impact of this newly understood mechanism.
"This is a fundamental breakthrough in our understanding of how the immune system is turned off and on in cancer," stated Dr. Engleman in a press release. "I could not be more excited about this discovery, and I hope treatments that target the mechanism we uncovered will quickly move forward to human trials." The implications of this research extend far beyond liver cancer, with strong indications that EPO’s immunosuppressive role is operative in a wide array of human malignancies.
The Unexpected Role of Erythropoietin
For decades, EPO has been a well-established therapeutic agent, primarily prescribed to patients suffering from anemia, often associated with chronic kidney disease or chemotherapy. Its ability to stimulate the bone marrow to produce more red blood cells has been a cornerstone of managing blood disorders. However, the darker side of EPO’s influence in the context of cancer has been lurking in the shadows of scientific literature.
As far back as 2007, the U.S. Food and Drug Administration (FDA) mandated a black box warning for EPO-stimulating agents, cautioning against their use in cancer patients. This warning was prompted by observations that EPO administration could accelerate tumor growth in these individuals. Further research from over a decade ago had already established a correlation between higher levels of naturally occurring EPO and its receptor (EPOR) within tumors and poorer patient prognoses across various cancer types. "Those old reports showed clearly that the more EPO or EPOR there was in tumors, the worse off the patients were," Dr. Engleman noted. "But the connection between EPO and cancer immunity was never made until now. In fact, it took a long time and a lot of experiments to convince us that EPO plays a fundamental role in blocking the immune response to cancer, because EPO is so well established as a red blood cell growth factor."
Unraveling the Mechanism in Mouse Models
To meticulously investigate this complex interplay, Dr. Chiu developed sophisticated mouse models of liver cancer. These models were designed to accurately recapitulate specific mutations, histological characteristics, and responses to existing therapies observed in human liver cancers. Tumorigenesis was induced either by injecting DNA encoding cancer-associated proteins directly into the animals’ tail veins or by implanting established liver cancer cells into their livers.
A key focus of the research was the efficacy of a common immunotherapy known as anti-PD-1 therapy. This treatment targets the PD-1 molecule on T cells, a critical component of the immune system responsible for identifying and destroying cancer cells. By binding to PD-1, cancer cells can evade immune surveillance. Anti-PD-1 therapies, such as the widely used Keytruda, have transformed outcomes for patients with certain cancers like melanoma and lung cancer. However, a significant challenge remains: a large proportion of tumors, including many liver, pancreatic, colon, breast, and prostate cancers, are inherently resistant to these treatments.
The researchers observed that, mirroring human liver cancers, certain genetic mutations in the mouse models led to the development of "cold" tumors. These tumors were largely ignored by the immune system, existing in an "immune-privileged" state. Consequently, anti-PD-1 therapy proved ineffective, as there were very few T cells present within these tumors to be activated. In contrast, tumors arising from different mutations were characterized as "hot," meaning they were heavily infiltrated with T cells and highly responsive to anti-PD-1 treatment, which then successfully triggered the immune cells to attack the cancer.
The EPO-Hypoxia Connection
A pivotal finding emerged when the researchers compared the EPO levels in these distinct tumor types. They discovered that cold tumors exhibited significantly elevated levels of EPO compared to their hot counterparts. This increase was strongly linked to the oxygen-poor microenvironment, a condition known as hypoxia, which is prevalent in many cold tumors. Hypoxia triggers cancer cells to produce proteins that, in turn, upregulate EPO production. The rationale, previously understood, was that this EPO surge aimed to stimulate red blood cell formation to combat the low oxygen levels. "Hypoxia in tumors has been studied for decades," Dr. Engleman remarked. "It just didn’t dawn on anyone, including me, that EPO could be doing anything in this context other than serving as a red blood cell growth factor."
To validate the broader relevance of this observation, the research team consulted existing databases and confirmed a significant correlation between elevated EPO levels and poorer survival rates in patients with liver, kidney, breast, colon, and skin cancers.
Manipulating EPO and its Impact on Tumor Immunity
The most compelling evidence for EPO’s role in immune suppression came from experiments where the researchers genetically modified tumor cells to alter their EPO production. They found that when mutations that typically led to cold tumors were engineered to prevent EPO production, the tumors transformed into hot tumors. Conversely, hot tumors that were previously eradicated by the immune system began to thrive when engineered to produce elevated levels of EPO.
Further in-depth investigations revealed the precise mechanism by which EPO exerts its immunosuppressive effects in cold tumors. Tumor cells secrete EPO, which then binds to receptors on the surface of macrophages, a type of immune cell. This binding prompts macrophages to adopt an immunosuppressive phenotype, effectively repelling cancer-killing T cells and dampening their activity. This intricate crosstalk between tumor cells and macrophages, orchestrated by EPO, is crucial for immune evasion.
Synergistic Therapeutic Potential
The significance of this EPO-mediated immunosuppression became unequivocally clear when the researchers examined the combined effect of simultaneously blocking the EPO signaling pathway and the anti-PD-1 pathway. In these critical experiments, mice with cold liver tumors that received only control treatment or anti-PD-1 therapy alone survived for no more than eight weeks post-tumor induction. However, a dramatic shift occurred when the EPO signaling pathway was disrupted. Mice with macrophages unable to produce the EPO receptor showed significantly improved survival, with 40% living for 18 weeks, the duration of the experiment. When anti-PD-1 treatment was administered to these mice lacking the EPO receptor, an astonishing 100% survival rate was achieved for the entire experimental period.
"It’s simple," Dr. Engleman explained. "If you remove this EPO signaling, either by lowering the hormone levels or by blocking the receptors on the macrophages, you don’t just get a reduction in tumor growth, you get tumor regression along with sensitivity to anti-PD-1 treatment." This finding underscores the potential of dual-targeting strategies to overcome resistance to current immunotherapies.
Future Directions and Broader Implications
The implications of this discovery are profound, suggesting a universal mechanism of immune suppression that could be targeted across a wide spectrum of cancers. Dr. Engleman and his team are actively engaged in designing therapeutic interventions that specifically target EPO signaling in human cancers.
Two primary therapeutic approaches are being considered. The first involves non-specifically targeting the EPO protein itself. While this could potentially lead to anemia, a manageable side effect, Dr. Engleman speculates that this trade-off might be acceptable for achieving effective cancer therapy. The second, more targeted approach, focuses on selectively blocking the EPO receptors on the surface of immunosuppressive macrophages within the tumor microenvironment. This strategy aims to preserve EPO’s essential red blood cell-stimulating function while neutralizing its detrimental effects on anti-cancer immunity.
"I continue to be amazed by this finding," Dr. Engleman expressed. "Not every tumor is going to respond in the same way, but I’m very optimistic that this discovery will lead to powerful new cancer therapies."
The research was a collaborative effort involving contributions from the New York Blood Center and the pharmaceutical company ImmunEdge Inc. Funding for this pivotal study was provided by the National Institutes of Health, with grants R01CA262361, P01CA244114, U54CA2745115, and P01HL149626. Notably, Dr. Chiu is a co-founder of ImmunEdge Inc., and Dr. Engleman is a founder, shareholder, and board member of the company. Both are affiliated with Stanford University as inventors on PCT/US2023/063997, a patent application titled "EPO receptor agonists and antagonists," further signaling their commitment to translating this discovery into clinical applications.
This research represents a significant leap forward in cancer immunology, offering a new paradigm for understanding and combating a disease that continues to pose a major global health challenge. The identification of EPO as a key immunosuppressive agent in cancer opens exciting avenues for developing novel, more effective treatments that could offer hope to millions of patients worldwide.
