By Lina carolina 
A protein identified nearly 40 years ago for its ability to stimulate the production of red blood cells plays a surprising, critical role in dampening the immune system’s response to cancer. This groundbreaking discovery, detailed in a study published online April 24 in the esteemed journal Science, has revealed a novel therapeutic target with the potential to transform the treatment of numerous cancers. Researchers have found that by blocking the activity of this protein, erythropoietin (EPO), formerly "cold," or immune-resistant, liver tumors in mice were converted into "hot" tumors teeming with cancer-fighting immune cells. This approach, when combined with existing immunotherapy that further activates these immune cells, led to the complete regression of existing liver tumors in the majority of treated mice, with the animals surviving for the duration of the experimental period. In stark contrast, control animals in the study survived only a few weeks, underscoring the profound impact of this discovery.
Unraveling the Immune Evasion Mechanism of Cancer
The protein in question, erythropoietin (EPO), has long been recognized for its vital role in stimulating the production of red blood cells, a function critical for oxygen transport throughout the body. Its discovery dates back to the early 1980s, revolutionizing the treatment of anemia. However, this new research, spearheaded by Edgar Engleman, MD, PhD, a professor of pathology and of medicine, and lead author David Kung-Chun Chiu, PhD, a basic life research scientist, unveils an unexpected and significant role for EPO in the complex interplay between cancer and the immune system.
"This is a fundamental breakthrough in our understanding of how the immune system is turned off and on in cancer," stated Dr. Engleman. "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 research builds upon decades of prior observations that, in retrospect, hinted at EPO’s involvement in cancer progression. As far back as a decade ago, studies indicated that administering EPO to cancer patients suffering from anemia to boost red blood cell formation paradoxically accelerated tumor growth. This correlation was so pronounced that in 2007, the U.S. Food and Drug Administration (FDA) mandated a black box warning on EPO-based drugs, cautioning against their use in individuals with cancer. Further analysis of patient data revealed a clear correlation between higher levels of naturally occurring EPO and its receptor (EPOR) within tumors and poorer patient prognoses.
"Those old reports showed clearly that the more EPO or EPOR there was in tumors, the worse off the patients were," Dr. Engleman explained. "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."
The Genesis of the Discovery: Mouse Models and Immunotherapy
The current study leveraged sophisticated mouse models of liver cancer, meticulously developed by Dr. Chiu using advanced genome editing techniques. These models were designed to recapitulate specific mutations, histological features, and responses to therapies observed in various subtypes of human liver cancers. Tumor formation was induced either by injecting DNA encoding proteins associated with liver cancer or by implanting liver cancer cells directly into the animals’ livers.
A central focus of the research was the impact of a common immunotherapy targeting a molecule called PD-1, found on T cells, a crucial component of the immune system. The binding of PD-1 to its receptor on other immune cells effectively acts as a "brake," suppressing T cell activity and allowing cancer cells to evade immune detection. Immunotherapies that block this PD-1 pathway, such as the widely used drug Keytruda, have revolutionized the treatment of certain cancers, including melanoma, Hodgkin’s lymphoma, and some lung cancers. However, a significant challenge remains: a large proportion of tumors, including many common types like liver, pancreas, colon, breast, and prostate cancers, are resistant to these therapies.
The researchers observed that in their mouse models, certain combinations of genetic mutations led to the development of liver tumors that were largely ignored by the immune system. These "cold" tumors, characterized by a scarcity of cancer-fighting T cells, did not respond to anti-PD-1 treatment. In contrast, tumors arising from other mutations were "hot," meaning they were infiltrated by T cells and were highly sensitive to anti-PD-1 therapy, which successfully activated the T cells to attack the cancer.
The Unexpected Link: Hypoxia, EPO, and Immune Suppression
A key finding emerged when the researchers compared the molecular profiles of cold and hot tumors. They discovered that cold tumors exhibited significantly elevated levels of EPO. This increase was traced back to the oxygen-poor microenvironment, a condition known as hypoxia, commonly found in rapidly growing tumors. Hypoxia triggers cancer cells to produce proteins that, in turn, upregulate EPO production, aiming to stimulate red blood cell formation to combat the low oxygen.
"Hypoxia in tumors has been studied for decades," Dr. Engleman noted. "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 this unexpected link, the team consulted existing scientific databases, confirming that elevated EPO levels correlate with poorer survival rates in patients with liver, kidney, breast, colon, and skin cancers. Their subsequent experiments involved genetically modifying tumor cells to alter their EPO production. The results were striking: when cold tumors were engineered to be unable to produce EPO, they transformed into hot tumors. Conversely, hot tumors, which were previously eradicated by the immune system, thrived when engineered to produce elevated levels of EPO.
Further detailed investigations revealed the precise mechanism by which EPO exerts its immunosuppressive effect. In cold tumors, cancer cells secrete EPO, which then binds to receptors on the surface of immune cells called macrophages. These macrophages, upon encountering EPO, shift from a potentially anti-tumor role to an immunosuppressive one, actively repelling cancer-killing T cells and dampening their activity. This EPO-mediated crosstalk between tumor cells and macrophages is critical for establishing the immune-resistant environment characteristic of cold tumors.
The Power of Combination Therapy: Blocking EPO Signaling
The significance of this EPO-driven immune suppression became dramatically clear when the researchers studied the combined effect of simultaneously blocking both the EPO signaling pathway and the PD-1 pathway. In mice with cold liver tumors that received either a control treatment or only anti-PD-1 therapy, survival was limited to less than eight weeks post-tumor induction. However, a remarkable transformation occurred when the EPO signaling pathway was disrupted. Mice whose macrophages were engineered to lack the EPO receptor survived for 18 weeks, the duration of the experiment. Furthermore, when anti-PD-1 treatment was administered to mice lacking the EPO receptor, all animals survived for the entire experimental period, indicating complete tumor eradication.
"It’s simple," Dr. Engleman emphasized. "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."
Future Directions and Broader Implications
This pivotal discovery opens up exciting new avenues for cancer therapy. Dr. Engleman and his colleagues are actively designing treatments aimed at targeting EPO signaling in human cancers. One potential approach involves non-specifically targeting the EPO protein itself. While this might lead to anemia, a side effect that Dr. Engleman speculates could be an acceptable trade-off for an effective cancer treatment, another strategy focuses on selectively blocking the EPO receptors on macrophages within the tumor microenvironment. This more targeted approach could potentially mitigate systemic side effects.
The implications of this research extend beyond liver cancer. Given the strong indications that EPO plays a similar role in a wide range of human cancers, this discovery holds the promise of becoming a broadly applicable therapeutic strategy. The fact that EPO is already a well-established therapeutic target for anemia means that considerable knowledge about its pharmacokinetics and potential side effects already exists, potentially accelerating the translation of these findings into clinical practice.
"I continue to be amazed by this finding," Dr. Engleman stated. "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 scientists from the New York Blood Center and the pharmaceutical company ImmunEdge Inc. Funding for the study was provided by the National Institutes of Health, with grants R01CA262361, P01CA244114, U54CA2745115, and P01HL149626. Notably, Dr. Chiu is a cofounder of ImmunEdge Inc., and Dr. Engleman is a founder, shareholder, and board member of the company. Both are also listed as inventors on a patent application related to EPO receptor agonists and antagonists, highlighting their significant contributions to the field and their commitment to developing novel therapeutic solutions. This breakthrough underscores the importance of fundamental scientific inquiry and the potential for unexpected discoveries to emerge from studying long-known biological molecules in new contexts.
