A new weapon that leukemia patients' cancer cells use to evade attacks from the immune system has been found. Previously, researchers discovered a decoy signal that tricks the immune system into mistaking cancer cells for normal cells, but the newly identified weapon is a coating membrane that directly blocks immune cell attacks, like the vibranium shield of the cartoon character Captain America. The same shield appears to exist not only in blood cancers but also in other cancers, raising hopes for a breakthrough in cancer treatment.
A research team led by Todd Golub of the Broad Institute said on the 9th (local time) in the journal Science that it confirmed leukemia cells form a physical barrier with a surface glycoprotein called CD43 to block attacks from immune cells. The Broad Institute is a life sciences research organization jointly founded by Harvard University and MIT.
◇ Alternative proposed for treating acute leukemia
Leukemia is a blood cancer in which white blood cells proliferate abnormally in the bone marrow inside bones and prevent the production of blood cells such as red blood cells, platelets, and white blood cells. Scientists previously learned that cells with blood cancer have a surface protein called CD47 that helps them evade the immune system's attacks. Macrophages, a type of immune cell, devour cancer cells and external invaders. CD47 on blood cancer cells acts as a signal to macrophages to "don't eat me."
The problem is that drugs designed to block CD47 work well for other cancers but are not effective for patients with acute myeloid leukemia (AML). To find out why, scientists at the Broad Institute analyzed thousands of genes that produce proteins in leukemia cells. Using the CRISPR-Cas9 gene-editing tool, which can cut desired regions of DNA at will, they knocked out genes one by one and observed macrophage responses.
In experiments, when the gene that produces CD43 was blocked, macrophages again devoured the cancer cells. CD43 had been blocking macrophage attacks, but researchers had mistakenly targeted CD47 and failed to treat acute myeloid leukemia. Contrary to expectations, CD43 did not send a "don't eat me" signal to macrophages like CD47. The team found that immune cells could not physically approach cancer cells surrounded by the CD43 glycoprotein.
CD43 is a long glycoprotein chain. It was as if the surface of the cancer cell were encircled by thorn bushes. In experiments, when researchers altered the CD43 gene to shorten the length of the glycoprotein chain, macrophages more easily engulfed the cancer cells. As the thorns shortened, the body's defenders could more easily get over the fence and attack.
When CD43 was suppressed in leukemia cells, the killing power of immune cells including not only macrophages but also T cells and natural killer (NK) cells increased. While CD47 delivered false information that blocked only the phagocytic activity of macrophages, CD43 served as a physical barrier that blocked immune cells regardless of type.
◇ Opening a new path for cancer immunotherapy
The researchers believe other cancer cells also erect a thick glycoprotein shield to evade immune attacks. In fact, when CD43 in leukemia cells was replaced with MUC1, a glycoprotein commonly found in other cancer cells, the same barrier effect that blocked immune cells appeared.
The team said, "We think we have discovered a fundamental principle of immune evasion that operates in almost all cancers," and noted, "If we figure out how to dismantle it, we may be able to treat not only leukemia but other cancers with immune cells." Just as they targeted CD43 to treat acute myeloid leukemia, they plan to attack glycoproteins that form physical barriers in other cancers to achieve therapeutic effects. Efficacy could be amplified by simultaneously targeting CD47, which confuses macrophages.
The researchers are currently searching for antibodies that bind to CD43. If macrophages pass by without seeing cancer cells hidden behind the CD43 barrier, the plan is for antibodies to find CD43 and alert macrophages that there are cancer cells inside. In the lab, using this approach made it easier for macrophages to find and devour leukemia cells, the team said.
References
Science (2026), DOI: https://doi.org/10.1126/science.ady5196