By Lina carolina 
A protein initially identified nearly four decades ago for its pivotal role in stimulating the production of red blood cells has been revealed to possess a surprising and critical function: dampening the immune system’s ability to combat cancer. This groundbreaking discovery, detailed in a recent study published in the esteemed scientific journal Science, offers a novel perspective on cancer immunology and opens promising avenues for the development of more effective cancer therapies.
Unlocking Immune Resistance in Liver Tumors
The research, spearheaded by Dr. Edgar Engleman, MD, PhD, a distinguished professor of pathology and medicine, and lead author Dr. David Kung-Chun Chiu, PhD, a basic life research scientist, has demonstrated that inhibiting the activity of this protein, known as erythropoietin (EPO), can transform previously "cold" or immune-resistant liver tumors in mice into "hot" tumors. These "hot" tumors are characterized by a dense infiltration of cancer-fighting immune cells, specifically T cells, which are crucial for mounting an effective anti-tumor response.
In a series of compelling experiments, the researchers combined the blocking of EPO activity with an established immunotherapy that further activates these immune cells against cancer. This dual approach led to the complete regression of existing liver tumors in a significant majority of the treated mice. Remarkably, these treated animals survived for the entire duration of the experimental period. In stark contrast, control groups of mice with untreated tumors succumbed to the disease within a few weeks, highlighting the profound therapeutic potential of this newly uncovered mechanism.
"This is a fundamental breakthrough in our understanding of how the immune system is turned off and on in cancer," stated Dr. Engleman, expressing his profound enthusiasm for the discovery. "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."
A Historical Perspective on Erythropoietin
Erythropoietin (EPO) has been a well-established player in human physiology since its discovery in the 1970s. Its primary function is to signal the bone marrow to increase the production of red blood cells, a process vital for oxygen transport throughout the body. For decades, EPO has been medically utilized to treat anemia, a condition characterized by a deficiency of red blood cells, particularly in patients with chronic kidney disease or undergoing chemotherapy.
However, observations over the past decade began to hint at a more complex relationship between EPO and cancer. Research indicated that administering EPO to cancer patients with anemia, while beneficial for their red blood cell count, paradoxically appeared to accelerate tumor growth. This correlation was so pronounced that by 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 also identified a clear link between elevated levels of naturally occurring EPO and its receptor 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 recalled. "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." This established understanding of EPO’s erythropoietic function made its newly revealed immunosuppressive role in cancer a truly unexpected and significant revelation.
Investigating Liver Cancer Models
To delve deeper into the role of EPO in cancer immunity, Dr. Chiu developed and utilized several sophisticated mouse models of liver cancer. These models were meticulously engineered to recapitulate specific genetic mutations, histological characteristics, and responses to approved therapies observed in various subtypes of human liver cancers. Tumor formation was induced either by injecting DNA encoding proteins associated with liver cancer into the animals’ tail veins or by implanting established liver cancer cells directly into their livers.
The researchers’ initial focus was on the impact of a common immunotherapy targeting a molecule called PD-1, found on T cells. PD-1 acts as an "off switch" for T cells, preventing them from attacking cancer cells. Therapies that block PD-1, such as the widely used drug Keytruda, have revolutionized cancer treatment for certain malignancies, including melanoma, Hodgkin’s lymphoma, and some lung cancers. However, a substantial proportion of tumors, including many liver, pancreatic, colon, breast, and prostate cancers, remain resistant to these treatments.
The study observed that, consistent with findings in 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, rendering them "immune privileged." Consequently, these cold tumors showed little to no shrinkage when treated with anti-PD-1 therapy, as very few T cells were present to mount an attack.
In contrast, other mutations resulted in "hot" or "inflamed" tumors, which were densely populated with T cells. These hot tumors proved highly sensitive to anti-PD-1 treatment, as the immunotherapy effectively unleashed the existing T cells to target and destroy the cancer.
The Unexpected Role of EPO in Tumor Microenvironments
A pivotal observation emerged when the researchers compared the EPO levels in cold versus hot tumors. They discovered that cold tumors exhibited significantly elevated levels of EPO compared to their hot counterparts. This increase was strongly correlated with the oxygen-poor microenvironment, a condition known as hypoxia, which is frequently prevalent in cold tumors. Hypoxia is known to induce the production of specific proteins within cancer cells that, in turn, can stimulate the production of EPO. The biological rationale for this is to increase red blood cell production to improve oxygen delivery to the starved tumor tissue.
"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 their hypothesis, the researchers consulted existing databases and confirmed that elevated EPO levels are indeed associated with poorer survival rates in patients with various cancers, including liver, kidney, breast, colon, and skin cancers. Their subsequent experimental manipulations provided compelling evidence of EPO’s direct role in immune suppression.
Rewiring Tumor Immunity: EPO as the Master Switch
The team then ingeniously modified the ability of tumor cells to produce EPO in their experimental models. They found that when mutations that typically led to cold tumors were altered to prevent EPO production, these tumors transformed into hot tumors. Conversely, hot tumors, which were previously susceptible to immune eradication, thrived and grew aggressively when engineered to produce elevated levels of EPO.
Further in-depth research elucidated the precise mechanism by which EPO exerts its immunosuppressive effects. In cold tumors, cancer cells secrete EPO, which then binds to receptors on the surface of immune cells called macrophages. These macrophages, upon activation by EPO, shift from a potentially anti-tumor role to an immunosuppressive one. They actively deter cancer-killing T cells from infiltrating the tumor microenvironment and suppress the activity of any T cells that do manage to enter.
This EPO-mediated crosstalk between tumor cells and macrophages proved to be a critical bottleneck for effective anti-cancer immunity. The researchers demonstrated this conclusively by studying the combined effect of simultaneously blocking the EPO signaling pathway and the PD-1 pathway.
Promising Therapeutic Strategies Emerge
The results of these combinatorial experiments were striking. Mice with cold liver tumors that received either a control treatment or anti-PD-1 therapy alone survived for no more than eight weeks after tumor induction. In contrast, mice with macrophages engineered to be unable to produce the EPO receptor lived for 18 weeks, the termination point 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 duration of the experiment, indicating a near-complete eradication of the tumors.
"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 discovery positions EPO as a key target for novel cancer therapies. Dr. Engleman and his colleagues are actively designing treatments aimed at modulating EPO signaling in human cancers. One potential strategy involves non-specifically targeting the EPO protein itself. While this could potentially lead to anemia as a side effect, Dr. Engleman speculates that this might be an acceptable trade-off for a highly effective cancer therapy. An alternative and potentially more precise approach is to selectively block the EPO receptors on the surface of macrophages within the tumor microenvironment, thereby sparing the systemic effects of EPO.
Broader Implications and Future Directions
The implications of this research extend far beyond liver cancer. Given the widespread presence of EPO and its receptor in various human cancers, and the observed correlation with poorer outcomes, the findings are likely applicable to a broad spectrum of malignancies. The study’s findings have generated significant excitement within the oncology research community, with many anticipating the rapid translation of these discoveries into clinical practice.
"I continue to be amazed by this finding," Dr. Engleman concluded. "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 supported by grants from the National Institutes of Health (NIH) and involved contributions from the New York Blood Center and the pharmaceutical company ImmunEdge Inc. Dr. Chiu is a co-founder of ImmunEdge Inc., and Dr. Engleman is a founder, shareholder, and board member of the same company. Both are affiliated inventors on a patent application related to EPO receptor agonists and antagonists, underscoring their deep involvement in this line of research. This multidisciplinary collaboration and investment in scientific inquiry are crucial for advancing our understanding and treatment of cancer. The long-term vision is to leverage this newfound knowledge to develop targeted therapies that can effectively reawaken the immune system’s dormant potential to fight cancer, offering hope to millions of patients worldwide.
