By Lina carolina 
A groundbreaking discovery is poised to revolutionize our understanding of cancer immunity and potentially pave the way for novel therapeutic strategies. Researchers have identified a critical, yet previously unrecognized, role for erythropoietin (EPO), a protein long known for its function in stimulating red blood cell production, in actively suppressing the immune system’s ability to combat cancer. This revelation challenges decades of established scientific dogma and offers a new avenue for treating notoriously difficult-to-treat "cold" tumors.
The study, published online on April 24 in the prestigious journal Science, details how blocking EPO’s activity transforms formerly immune-resistant liver tumors in mice into "hot" tumors, brimming with cancer-fighting immune cells. When this blockade was combined with existing immunotherapies that further activate these immune cells, the treatment resulted in the complete regression of existing liver tumors in the majority of the animal subjects. Treated mice survived for the duration of the experimental period, a stark contrast to the control group, which succumbed to the disease within weeks.
"This is a fundamental breakthrough in our understanding of how the immune system is turned off and on in cancer," stated Edgar Engleman, MD, PhD, a professor of pathology and of medicine and the senior author of the research. "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 lead author of the study, David Kung-Chun Chiu, PhD, a basic life research scientist, spearheaded the complex experimental work. Their findings suggest that EPO’s immunosuppressive function might be a widespread phenomenon across various cancer types, not limited to liver cancer.
The Unexpected Role of Erythropoietin in Cancer Immunity
For nearly four decades, EPO has been exclusively recognized for its role in erythropoiesis – the process of red blood cell production. This function is vital for oxygen transport throughout the body, and EPO is naturally produced by the kidneys in response to low oxygen levels. However, the current research reveals a hidden, immunosuppressive facet of this well-known hormone.
The investigation into EPO’s role in cancer immunity was born from observing a concerning correlation in human cancer patients. Research conducted over a decade ago indicated that administering EPO to cancer patients to treat anemia actually accelerated tumor growth. This observation was so significant that, in 2007, the U.S. Food and Drug Administration (FDA) mandated a black box warning on EPO-containing drugs, cautioning against their use in individuals with cancer. Further studies revealed a clear correlation between higher levels of naturally occurring EPO and its receptor within tumors and a poorer patient prognosis.
"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."
Unraveling the Mechanism in Mouse Models
To meticulously investigate this newfound link, Dr. Chiu developed and utilized several sophisticated mouse models of liver cancer. These models were designed to accurately recapitulate specific mutations, histological features, and responses to approved therapies found in various subtypes of human liver cancers. Tumor formation was induced either by injecting DNA encoding proteins associated with liver cancer directly into the animals’ tail veins or by implanting established liver cancer cells into their livers.
A key focus of the research was the impact of a common immunotherapy targeting the PD-1 molecule on T cells. PD-1 is a critical checkpoint protein on immune cells that cancer cells exploit to evade detection and destruction. Therapies that block PD-1, such as the widely used drug Keytruda, have transformed outcomes for patients with certain cancers, including melanoma, Hodgkin’s lymphoma, and some lung cancers. However, a significant limitation of these therapies is their ineffectiveness against a majority of tumors, including many liver, pancreatic, colon, breast, and prostate cancers. These resistant tumors are often characterized as "cold" – meaning they are largely devoid of cancer-fighting immune cells like T cells.
The researchers observed that, mirroring human liver cancers, certain combinations of mutations in their mouse models led to the development of "cold" tumors that were essentially ignored by the immune system. These immune-privileged tumors failed to respond to anti-PD-1 treatment because they lacked the necessary T cell infiltration. In contrast, tumors arising from other genetic mutations were classified as "hot" or "inflamed," teeming with T cells and highly susceptible to anti-PD-1 therapy.
The Hypoxia-EPO Connection
A pivotal discovery emerged when the researchers found that these "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 the production of specific proteins within cancer cells that, in turn, upregulate EPO production. The prevailing theory had been that this EPO surge was solely aimed at compensating for the low oxygen by increasing red blood cell numbers.
"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."
This unexpected finding prompted the researchers to delve deeper. They examined existing databases and confirmed that elevated EPO levels in human cancers of the liver, kidney, breast, colon, and skin were indeed correlated with poorer survival rates. Armed with this confirmation, they proceeded to genetically engineer tumor cells to manipulate their ability to produce EPO.
Rewiring Tumor Immunity: The Impact of EPO Manipulation
The results of these genetic modifications were striking. Tumors that had initially developed as "cold" and immune-resistant became "hot" when the tumor cells were engineered to be unable to produce EPO. Conversely, "hot" tumors, which were previously susceptible to immune attack, thrived and became more aggressive when engineered to produce elevated levels of EPO. This provided compelling evidence that EPO itself was actively contributing to the immune evasion of cancer cells.
Further extensive research elucidated the precise mechanism. In "cold" tumors, cancer cells secrete EPO, which then binds to receptors on the surface of macrophages, a type of immune cell. This interaction compels the macrophages to adopt an immunosuppressive role, effectively repelling cancer-killing T cells and dampening their activity. This intricate crosstalk between tumor cells and macrophages, orchestrated by EPO, creates a formidable barrier to effective anti-tumor immunity.
A Synergistic Approach to Cancer Treatment
The critical importance of this EPO-mediated communication was dramatically demonstrated when the researchers explored the combined effect of simultaneously blocking the EPO signaling pathway and the PD-1 pathway. In these experiments, mice with "cold" liver tumors treated with either a control substance or anti-PD-1 alone did not survive beyond eight weeks post-tumor induction. However, a remarkable 40% of mice whose macrophages were unable to produce the EPO receptor survived for 18 weeks, the full duration of the experiment. When anti-PD-1 treatment was administered to mice lacking the EPO receptor on their macrophages, all animals survived for the entire experimental period.
"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 Clinical Implications
The implications of these findings are profound. The research team is actively designing therapeutic strategies that target EPO signaling in human cancers. One potential approach involves non-specifically targeting the EPO protein itself. While this could lead to anemia, a manageable side effect, it might be a worthwhile trade-off for an effective cancer therapy. A more targeted approach involves selectively blocking the EPO receptors on the surface of macrophages within the tumor microenvironment, thereby preventing EPO from exerting its immunosuppressive effects.
"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 collaborative effort involved researchers from the New York Blood Center and the pharmaceutical company ImmunEdge Inc. This groundbreaking study was supported by grants from the National Institutes of Health (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, underscoring their significant contributions to this field.
This discovery represents a significant leap forward, transforming our understanding of how cancer cells can manipulate the immune system and offering a beacon of hope for patients with cancers that have historically resisted treatment. The translation of these findings into clinical trials could usher in a new era of cancer immunotherapy.
