Acute myeloid leukemia (AML) not only infiltrates the lungs but also transforms lung tissue to create an inflammatory environment that promotes tumor cell expansion and impairs respiratory function, according to a study published in Nature Immunology. The research was co-led by Dr. Manel Esteller, ICREA research professor and head of the Cancer Epigenetics Group at the Sant Pau Research Institute, and Dr. Iannis Aifantis of New York University Grossman School of Medicine.
The researchers used single-cell and spatial transcriptomics, experimental animal models, human samples, and clinical data to observe that leukemia cells accumulate in alveolar and vascular regions of the lungs. This accumulation disrupts capillary integrity and alters both structural cells and immune responses within lung tissue. The study identified galectin-9 and the IL-33/IL1RL1 axis as potential targets for reducing these complications.
Dr. Esteller said, "The first thing we observed was that when leukemia cells reach the lungs, they alter the function of the organ's different cell types. They do not simply invade the tissue; they create a niche—an environment that supports their persistence and expansion." He further explained that this process involves extensive remodeling of lung architecture with increased vascular permeability, reduced endothelial cells essential for gas exchange, greater collagen deposition indicating fibrosis, and changes in immune cell populations.
Functional experiments confirmed these changes led to impaired respiratory capacity in animals with AML-related lung infiltration. The inflammatory response extended throughout lung tissue rather than being confined to areas around tumor cells. According to Dr. Esteller, "Tumor cells establish a network of interactions with the cells surrounding them. This communication alters both the lung structure and the local immune response and helps amplify inflammation." Analysis showed increases in neutrophils, interstitial macrophages, nonclassical monocytes—cells involved in inflammation—while T lymphocytes decreased.
Blocking galectin-9 or interfering with IL-33/IL1RL1 signaling reduced leukemic infiltration as well as inflammation in animal models; it also improved survival outcomes by restoring certain immune functions such as B cell presence while decreasing exhausted T cells' proportion. Prednisone treatment likewise reduced leukemic burden in animal models' lungs; retrospective analysis showed eight patients experienced rapid improvement after receiving prednisone for AML-associated respiratory failure.
The authors concluded that understanding how AML remodels tissues outside bone marrow opens new therapeutic possibilities targeting not only leukemia itself but also its interaction with infiltrated organs: "Lung infiltration is the result of a complex relationship between leukemia cells and tissue cells... Understanding this communication allows us to identify vulnerable points," said Dr. Esteller.
