Blocking a surprising master regulator of immunity eradicates liver tumors in mice

Curious, the researchers turned to existing databases to confirm that elevated levels of EPO are correlated with poorer survival of people with cancers of the liver, kidney, breast, colon and skin. They then tinkered with the ability of the tumor cells to make EPO and were surprised at what happened in the animals’ liver tumors.

From cold to hot

They found that mutations that had led to the development of cold tumors instead caused hot tumors when the tumors were modified to be unable to make EPO. Conversely, hot tumors that had previously been successfully eradicated by the immune system thrived when they were engineered to make elevated levels of EPO.

Further exhaustive research showed that, in cold tumors, the tumor cells make and secrete EPO, which binds to receptors on the surface of immune cells called macrophages. The macrophages then switch to an immunosuppressive role, shooing away cancer-killing T cells and tamping down their activity.

The importance of this EPO-moderated crosstalk between tumor cells and macrophages showed clearly when the researchers studied the combinatorial effect of simultaneously blocking the EPO signaling pathway and anti-PD-1 pathway.

In those experiments, no mice with cold liver tumors that were treated with control or with anti-PD-1 lived more than eight weeks after tumor induction. In contrast, 40% of mice with macrophages unable to make the EPO receptor lived for 18 weeks after tumor induction, when the experiment was terminated. When anti-PD-1 treatment was given to mice lacking the EPO receptor, all animals lived for the duration of the experiment.

“It’s simple,” Engleman said. “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-1treatment.”

Engleman and his colleagues are now designing treatments targeting EPO signaling in human cancers. Non-specifically targeting the EPO protein could cause anemia, which Engleman speculates might be an acceptable trade-off for an effective cancer therapy. An alternative approach is to selectively block the EPO receptors on the surfaces of macrophages in the cancer.

“I continue to be amazed by this finding,” Engleman said. “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.”

Researchers from the New York Blood Center and the pharmaceutical company ImmunEdge Inc. contributed to the research.

The study was funded by the National Institutes of Health (grants R01CA262361, P01CA244114, U54CA2745115 and P01HL149626).

Chiu is a cofounder of ImmunEdge Inc. Engleman is a founder, shareholder and board member of ImmunEdge Inc. Chiu and Engleman are Stanford-affiliated inventors of PCT/US2023/063997, entitled “EPO receptor agonists and antagonists.”