Protein switch becomes hot tumor heat

The proteins known for their role in blood cell production have long been revealed as a major regulator of cancer immune response, providing potential game-changers for previously untreated liver tumors.

Stanford Medicine researchers found in a reversal of amazing scientific expectations that erythropoietin (EPO) stimulated the production of red blood cells about 40 years ago, and actually played a crucial role in suppressing the immune system’s ability to fight cancer.

The breakthrough study, published scientifically on April 24, reveals that EPO blockage transforms previously immune “cold” liver tumors in mice into “hot” tumors filled with anti-cancer immune cells. When this approach is used in combination with existing immunotherapy, the results are significant.

“This is a fundamental breakthrough in our understanding of how the immune system shuts down cancer,” said Dr. Edgar Engleman, a professor of pathology and medicine at Stanford University and senior author on study. “I’m excited about this discovery and I hope that treatments targeting the mechanisms we’ve found will move forward quickly.”

These findings solved a mystery that confused cancer researchers for more than a decade. In 2007, the FDA asked for a black box warning for EPO drugs that warned them to use in cancer patients after research showed they accelerated tumor growth. So far, scientists cannot explain why.

The research team, led by Dr. David Kung-Chun Chiu, a scientist in basic life research, found that in “cold” tumors, cancer cells produce and secrete EPO, which binds receptors to immune cells called macrophages. These macrophages then turn into immunosuppressive effects, preventing the cancer-killing T cells from attacking the tumor.

The results were dramatic when the researchers blocked the EPO pathway in mice with liver cancer and combined it with anti-PD-1 immunotherapy, similar to the drug keytruda used by humans. Although the lifespan of untreated mice was less than eight weeks, all mice treated with the combined treatment survived the duration of the 18-week experiment, and in most cases the tumor regression completely subsided.

“It’s very simple,” Engleman explained. “If you remove this EPO signaling by lowering hormone levels or blocking receptors on macrophages, you can not only reduce tumor growth, but also gain tumor regression and sensitivity to combat PD-1 treatment.”

This discovery is of great significance to human cancer treatment. Many aggressive cancers, including most liver, pancreatic, colon, breast and prostate tumors, show resistance to current immunotherapy precisely because they are “cold” – lacking enough immune cell infiltration.

An analysis of existing databases by Stanford University confirmed that elevated EPO levels are associated with poor survival rates for multiple cancer types, including liver, kidney, breast, colon and skin cancer.

Mechanically, the researchers found that EPO works through a complex signaling pathway called NRF2 (Nuclear Factor Red blood cell 2-associated factor 2), which drives changes in macrophages, thus making it immunosuppressed. This new understanding of discovery offers multiple potential goals for drug development.

In a perspective article in science, Dr. Priscilla N. Kelly noted that the EPO/EPO receptor pathway “can therefore serve as a switch to switch cancer immunity,” highlighting the potential implications of this finding for future treatment.

Face challenges. Nonspecific targeting of EPO may cause anemia, although Engleman speculates that this may be an acceptable trade-off for effective cancer treatment. Another approach explored is to selectively block EPO receptors on macrophages in the tumor environment.

This work represents a paradigm shift in understanding cancer immunology. While cancer researchers have long been studying hypoxia (low oxygen conditions) in tumors, no one associates the point between hypoxia, EPO production, and immunosuppression.

“The hypoxia in tumors has been studied for decades,” Engman noted. “EPO is not aware of it except as a red blood cell growth factor.”

When Engleman and his team worked to design treatments for EPO signals in human cancer, the discovery offered new hope for difficult-to-treat tumors. For patients with immunotherapy cancer, this previously overlooked protein may be key to making their body target the immune system that targets its disease.

“I’m still surprised by this discovery,” Engelman said. “Not every tumor will respond in the same way, but I’m very optimistic that this discovery will lead to a powerful new cancer therapies.”

The study was funded by the National Institutes of Health. Chiu is the co-founder of Immunedge Inc. Engleman is the founder, shareholder and board member of Immunedge Inc.