Led by NYU Langone Health researchers, a new study shows how blood cancer cells enter the lungs, damage tissue, and cause severe breathing problems. Published online June 29 in Nature Immunology, the new work addresses acute myeloid leukemia, or AML, a cancer in which cells in the bone marrow that would normally become blood cells instead start to multiply abnormally.
Respiratory failure is a common early AML complication caused by cancer cells infiltrating the lungs, but this process has been poorly understood. The researchers say reducing early breathing crises is crucial to giving AML therapies time to be effective.
By examining lung tissue slices from mice, as well as tissue biopsies of patients with AML lung "involvement," the study authors found that AML cancer cells infiltrate the lungs through the thin alveolar wall blood vessels, leaking into connective tissue (stroma). Once there, the AML cells change the structure of the stroma by increasing the number of fibroblasts, cells that produce the collagen that provides the strength and elasticity required for breathing. As part of AML, the overactivity of such cells creates scarlike tissue (fibrosis) that hinders breathing.
The study's tests also showed that AML-driven structural changes affect the mix of immune cells in the lungs, with a shift away from cell populations that attack cancer cells (e.g., lymphocytes) and toward myeloid cells that dial down immune attack. Further, the study showed that the presence of AML cells came with a significant drop in the number of endothelial capillary aerocytes, cells that enable the lungs to supply oxygen to the bloodstream as part of breathing.
There has been a lack of understanding in our field as to how leukemia cells invade the lungs, why they trigger respiratory crises, and why steroids counter this to some degree. Our results describe for the first time specific molecular targets that reduce lung infiltration, which new, better-tailored drug classes can be designed against."
Iannis Aifantis, PhD, chair of the Department of Pathology at NYU Grossman School of Medicine and a member of NYU Langone's Perlmutter Cancer Center
Another key finding stemmed from the research team's analysis of past AML cases. Steroid treatment is frequently used when a patient has a breathing crisis, based on doctors' educated guesses or experience rather than on scientific test results. In their analysis, the researchers found that all patients treated with prednisone when their breathing worsened due to leukemic lung infiltration showed dramatically improved respiratory function within 12 hours.
Newfound mechanisms become drug targets
Because AML cells arise in bone marrow, previous studies have examined their relationship to immune cells in the marrow, but not in the lungs. In the current study, the researchers combined single-cell, spatial, and functional experiments to unravel interactions between AML and its microenvironment in the lungs.
For instance, they used single-cell transcriptomics, a technique that measures the activity of genes in individual cells. By capturing the active genetic signals (e.g., mRNA sequences) of thousands of individual cells simultaneously, it reveals cellular diversity and identifies rare cell types. They also used spatial transcriptomics to map the exact locations in tissues where genes were active, as cells behave differently based on their neighbors.
Through mapping the interactions between cell types in leukemic lungs, the team identified two proteins as drivers of widespread lung inflammation that interferes with breathing. One was galectin-9, which binds sugar molecules on cell surfaces and helps them communicate. The other was the interleukin-33 (IL-33) receptor protein on the surface of leukemia cells. This protein passes on signals in damaged lung tissue when it docks into its receptor.
The researchers found that more galectin-9 is produced in AML cells because of the inflammation and the cell-cell interactions in the infiltrated lungs. Higher-than-normal levels of IL-33 receptor signaling were also present in the lungs of AML patients.
The study authors showed that blocking the action of either of these signaling pathways stops infiltration of AML cells into the lungs by affecting both immune cells and cancer cells. Along these lines, a phase 1 clinical trial (NCT05829226) is testing whether a first-of-its-kind antibody treatment that targets galectin-9 can combat AML.
"Our results provide first-time evidence that early steroid treatment should go from something that doctors try based on judgment calls to a treatment guideline in the field that saves lives," said Varvara Paraskevopoulou, PhD, an instructor in the Department of Pathology at NYU Grossman School of Medicine. "Our next step is to determine whether combining galectin-9 blockade with standard chemotherapy or targeted therapies provides added value in clinical settings."
The American Cancer Society estimates that 23,000 people will be diagnosed with AML in 2026, and that 11,500 will die from it.
This research was supported by the National Institutes of Health grants R01CA173636, R01HL159175, R01CA271455, R01CA283574, R01CA298153PAR22114, R01PAR24277, R01CA283574, R01PAR18896, R01CA262496, R01DK188072, R01AG069010, and U01AG077925. Also supporting the work were the Vogelstein Family Foundation, EvansMDS, the Taub Foundation, EMBO Postdoctoral Fellowship ALTF-742-2020, the Spanish Ministry of Science and Innovation, the Cellex Foundation, "la Caixa" Foundation, the European Regional Development Fund, the American Cancer Society, the Leukemia Research Foundation, the Pew Latin American Fellows Program, the American Society of Hematology Minority Award, and Blood Cancer United. The Experimental Pathology Research Laboratory at NYU Langone was supported by Perlmutter Cancer Center support grants P30CA016087 and P30CA016087.
Along with Drs. Aifantis and Paraskevopoulou, study authors from the Department of Pathology at NYU Langone were Wafa Al-Santli, MS; Juan Carlos Balandrán, PhD; Fang Zhou, MD; Ali Rashidfarrokhi, PhD; Michael Cross; Konstantinos Ntatsoulis, MSc; Tejas Patel, MD; Xufeng Chen, PhD; Thales Y. Papagiannakopoulos, PhD; Andre Da Luz Moreira, MD; and Aristotelis Tsirigos, PhD. Other NYU Langone authors were Stephen Yeung, PhD, and Kamal M. Khanna, PhD, in the Department of Microbiology and Ziyan Lin of Applied Bioinformatics Laboratories at NYU Grossman School of Medicine.
Dr. Aifantis is a consultant for Forsite Labs. Dr. Tsirigos is a scientific adviser to Intelligencia AI. These relationships are being managed in keeping with NYU Langone policy.
Study authors at other institutions were Marta Casado-Pelaez, Daniela Grases, Marc Escobosa, Eduard Porta, and co-corresponding author Manel Esteller of the Josep Carreras Leukaemia Research Institute in Badalona, Spain, as well as Deedra Nicolet and Ann-Kathrin Eisfeld of the Clara D. Bloomfield Center for Leukemia Outcomes Research at the Ohio State University Comprehensive Cancer Center, Jennifer Trowbridge of the Jackson Laboratory in Bar Harbor, Maine, and Rashmi Kanagal-Shamanna and Sanam Loghavi of the Department of Hematopathology at the University of Texas MD Anderson Cancer Center.
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