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Leukemia is adept at dodging the immune system, making it resistant to many of the newest generation of cancer immunotherapies. Now, researchers have identified a key part of the cancer’s disguise: a protein called CD43 on the surface of leukemia cells that is coated so heavily in sugar molecules that it forms a physical barrier, shielding the cells from immune attack.

The findings, from scientists at the ӳ����ý, Mass General Brigham, and Dana-Farber Cancer Institute, reveal a previously unrecognized way that cancer evades the immune system and could point toward new immunotherapies that block CD43 to expose cancer cells to immune attack.

“Discovering this phenomenon opens up a new avenue for cancer immunotherapy,” said Todd Golub, a Dana-Farber pediatric oncologist, director of the ӳ����ý and co-senior author of the study published in . “We think that the concept of cancers hiding behind sugar-coated proteins is not only important for leukemia, but likely other cancers as well.”

The team made this discovery by examining thousands of genes across the whole genome in leukemia cells, which uncovered a surprise about another protein called CD47 — the most well-known “don't-eat-me” signal used by cancers. They found that it had little effect on whether immune cells could destroy leukemia cells. The result could help explain why experimental drugs targeting CD47 have largely failed in clinical trials for patients with AML.

“We designed this experiment fully expecting that CD47 would be the most important protein for blocking the immune system,” said Robert Manguso, an associate member of the ӳ����ý and researcher at the with Mass General Brigham Cancer Institute, who co-led the study. “When it barely registered, we thought we’d made a mistake. We repeated the experiments over and over. But we kept getting the same answer.”

New options for AML

The new study arose out of conversations between the study’s co-first authors Jooho Chung, a postdoctoral researcher in the Manguso lab and a medical oncologist at Mass General Brigham Cancer Institute, and Mounica Vallurupalli, a Dana-Farber medical oncologist and postdoctoral researcher in the Golub lab at the ӳ����ý. Both physician-scientists were frustrated by the lack of options for their acute myeloid leukemia (AML) patients.

“We know that leukemia can be susceptible to immune attack, but we also know that most cases of AML don’t respond to the newer immunotherapies that have worked so well in other cancers,” said Chung. “We wanted to understand why.”

The researchers conducted a genome-wide CRISPR screen, disabling thousands of genes one-by-one in millions of human AML cells. Then, they tested which cells were recognized by macrophages—immune cells that patrol the body and destroy foreign or dangerous cells by engulfing them.

They found that AML cells that were missing CD43 were engulfed at dramatically higher rates than cells with functioning CD43. Cells lacking genes needed to coat CD43 with a sugar called sialic acid showed the same pattern. The results suggested that it was the sialic acid coating on CD43 that was protecting AML cells from macrophages.

Further experiments ruled out the possibility that CD43 was sending a specific molecular “don't-eat-me” signal to macrophages and pointed instead to a physical explanation for its ability to block immune reactions. The team suspected that the high levels of sugar-coated CD43 were completely blocking the ability of immune cells to get close to the surface of AML cells. 
Indeed, when Chung and Vallurupalli created progressively shorter versions of CD43 on AML cells, macrophages could more easily engulf the cells. The shorter the protein, the more effective the immune attack.

The team looked at other cancer-killing immune cells — T cells and NK cells — and discovered that inhibiting CD43 also enhanced their ability to attack AML cells.

“In every case we tried, all types of immune cells that need direct access to the cell surface were inhibited by high levels of CD43. And that really lent even more credibility to the idea that this is a physical barrier and not a specific interaction between a receptor and ligand,” Manguso said.

Toward new treatments

The researchers believe other cancers could also be covering themselves in large, sugar-coated proteins to fend off the immune system. When they replaced CD43 in AML cells with MUC1—a sugar-coated protein abundant in several cancer types—it produced the same barrier effect.

“We think we’re looking at a foundational layer of immune evasion that may be operating in nearly all cancers,” said Manguso. “Figuring out how to dismantle it has implications for cancer immunotherapy well beyond leukemia.”

The researchers are now exploring possible new treatments for AML by looking for antibodies that bind to CD43. In the lab, they found that this approach made it easier for macrophages to recognize and engulf AML cells.

“If we could block CD43 in just the right way, that could go a long way to developing a new therapeutic strategy to kill these cancer cells and treat leukemia,” Vallurupalli said.