Researchers at the MUSC Hollings Cancer Center have discovered a previously unrecognized autocrine signaling loop in acute myeloid leukemia (AML) that could serve as a new therapeutic target for this hard-to-treat blood cancer. The study, published in Nature Communications, shows that a stress-induced feedback loop between the protein IL-33 and its receptor IL1RL1 drives the self-renewal of leukemia stem cells (LSCs) and contributes to treatment resistance by creating an immunosuppressive environment.
“I’ve seen too many patients—especially children—suffer from AML,” said senior author Sophie Paczesny, MD, PhD, co-leader of the cancer biology and immunology research program at MUSC Hollings. “Unlike other forms of leukemia that respond well to chemotherapy or CAR-T cell therapy, AML has proven much more stubborn.”
AML is characterized by the rapid proliferation of immature myeloid cells in the bone marrow. A major barrier to effective treatment is the persistence of LSCs, which evade chemotherapy in bone marrow leading to disease relapse. Previous studies have pointed to the IL-33/IL1RL1 signaling axis as playing a role in hematopoietic and cancer biology, but its function in LSC maintenance and immune evasion in AML had not been thoroughly investigated.
In this study, the researchers used patient samples, public datasets, and preclinical models to demonstrate that IL1RL1 is highly expressed on AML cells, particularly LSCs, and correlates with poor prognosis and treatment resistance.
The researchers observed that IL-33 and IL1RL1 levels were elevated in AML cells under stress conditions, suggesting that hematopoietic stress may initiate the loop. Loss of IL1RL1 in genetically modified LSCs led to significant reductions in leukemogenesis, exhibited by decreased stemness in serial transplantation assays and a ~15-fold decrease in LSC function.
“At the core of this process, stem cell leukemogenesis initiation and maintenance signals are driven by a stress-induced IL-33/IL1RL1 autocrine loop,” the researchers wrote. This loop fosters an immune regulatory microenvironment that enables LSCs to evade attack by the immune system.
To test the therapeutic potential of targeting this loop, the team developed bispecific T-cell engaging antibodies (T-BsAbs) that simultaneously bind IL1RL1 and CD3 on T cells. This dual-targeting strategy was designed to both kill IL1RL1+ leukemia cells and activate cytotoxic T cells. In multiple mouse and human xenograft models of AML, T-BsAbs effectively reduced LSC populations, disrupted the immunosuppressive niche, and improved survival.
“These leukemia cells have learned to create a protective environment that helps them grow and avoid treatment,” Paczesny said. “We developed a bispecific antibody that can break through that environment and target the cells directly.”
Functional analyses revealed that IL-33-deficient LSCs also led to improved survival in mouse models and reduced proliferation. Disrupting this axis in LSCs altered the immune landscape by increasing CD8+ T cells specific for leukemia antigens and reducing immunosuppressive cells such as regulatory T cells (Tregs), MDSCs, and macrophages.
While AML has not shown susceptibility to CAR T cell-based immunotherapies, the researchers say their bispecific antibody approach has a significant advantage. “Our treatment is an off-the-shelf drug. And it targets cells just enough to fight cancer without destroying the whole system,” Paczesny said.
A significant factor is that IL1RL1 expression in healthy hematopoietic stem cells is minimal under non-stress conditions, which implies that therapies targeting IL1RL1 could preserve normal bone marrow function. Safety evaluations showed no colitis or off-target effects in treated mouse models, and in pediatric AML patient-derived xenograft (PDX) models, the anti-IL1RL1 T-BsAb reduced leukemic burden to undetectable levels.
The researchers said that further research is needed to address the heterogeneity of LSCs, noting that some may still evade treatment by entering a more quiescent state. Late relapses were observed in some models, indicating that while most AML cells are eliminated, a reservoir of resistant LSCs may persist.
The findings also have broader relevance since research has shown that IL1RL1 is expressed in colorectal, lung, ovarian, and brain cancers. The research team will now work to launch a Phase I clinical trial to test the safety and efficacy of IL1RL1-directed T-BsAb therapy in AML patients.
