Unlocking the Lung’s Ability to Heal: NK Cell Immunotherapy offers New Hope for Fibrosis
In pulmonary fibrotic diseases, the lung’s ability to regenerate and repair itself is severely impaired by the accumulation of pro-inflammatory “senescent” fibroblasts, damaged cells that block normal tissue repair, promote pathological scarring (fibrosis), and ultimately cause life-limiting respiratory decline.
Reactivating NK-cells through immunotherapy
New research now suggests there may be a way to eliminate these harmful cells by reactivating the body’s own natural killer (NK) cells, the immune system’s frontline assassins responsible for eliminating damaged, senescent cells. The study, spearheaded by Dr. Wolfgang Merkt, MD, at the University Hospital Heidelberg, and senior author Dr. David Lagares, PhD, MBA, former Harvard Medical School and Massachusetts General Hospital faculty member, shows that restoring NK-cell activity enables selective removal of senescent fibroblasts, reversal of lung fibrosis, and may reopen the lung’s natural capacity to regenerate.
Blocking NKG2A with Monalizumab
Partially supported by the German Society for Internal Medicine (DGIM), the study demonstrates that the first-in-class, clinical-grade immunotherapy Monalizumab can reactivate NK cells in vivo and clear senescent fibroblasts in preclinical mouse models of lung fibrosis, restoring lung function. The researchers also uncover why this approach works: NK cells from patients with fibrotic lung disease express high levels of NKG2A, an inhibitory checkpoint receptor that suppresses their ability to eliminate senescent fibroblasts, allowing these pathogenic cells to persist and drive scarring. By blocking NKG2A with Monalizumab, NK cells are released from this brake. In ex vivo human translational studies, the investigators show that Monalizumab robustly reactivates patient-derived NK cells and significantly enhances their ability to lyse human senescent fibroblasts in vitro.
Spectral flow cytometry at IfADo
Dr Maren Claus from the research group led by Prof. Dr Carsten Watzl at Leibniz Research Center for Working Environment and Human Factors (IfADo) in Dortmund, was able to use spectral flow cytometry to help understand the mechanism behind this therapy. Spectral flow cytometry can determine a wide range of parameters on individual cells simultaneously and with great precision. With the help of this analysis, the NK cells and fibroblasts in this study were characterised in detail and the interaction between NKG2A on NK cells and HLA-E on senescent fibroblasts was identified.
Restoring the lungs’ natural ability to heal
“Our findings suggest that by reactivating NK-cell surveillance, we may be able to eliminate senescent fibroblasts and reopen the road to lung regeneration, not only in idiopathic pulmonary fibrosis, but also in autoimmune disorders that develop lung fibrosis, such as systemic sclerosis and rheumatoid arthritis” says Dr. Merkt. “We identify defective NK-cell clearance of senescent fibroblasts as a core driver of lung fibrosis. This pathway is druggable with NK cell immunotherapy and opens a first-in-class strategy to reverse fibrosis by restoring the lung’s natural ability to heal,” adds Dr. Lagares, senior author of the study. The results of the study were published in Science Translational Medicine.