Excessive buildup of Langerhans cells in the body causes a rare and potentially fatal cancer-like inflammatory disease in children, called Langerhans cell histiocytosis (LCH). Langerhans cells are tissue-resident immune cells present in the bones, skin, lymph nodes, liver, and other tissues. Current treatment options for LCH require lifelong targeted therapy with significant side effects.

Immature and mutant Langerhans cells accumulate in tissues to form tumors called granulomas, leading some scientists to classify LCH as a form of cancer, but the nomenclature is controversial because pathological LCH cells remain in a unique balance between apoptosis and survival in an inflammatory niche. Cellular and molecular origins of LCH were reported in a study published in Science Immunology (“Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology”). The new findings could result in treatments that eliminate these pathological cells.

“In this study, the investigators take snapshots of LCH lesions at extremely high, single-cell, resolution and identify complex potential origins, differentiation, and dynamic interactions between activated pathologic DC and bystander cells,” said Carl Allen, MD, PhD, a professor of pediatric oncology at the Baylor College of Medicine. “Characterizing the origins and activities of the principal actors and supporting cast of immune cells that lead to LCH lesion formation and subsequent disease is an essential step to create and test rational therapeutic strategies for patients.” (Allen, who was not involved in the current study, reviewed recent advances in LCH research that he believes will propel LCH into the era of personalized medicine.)

“The origin of the LCH cells has been discussed for decades. Some researchers are convinced that LCH is derived from a certain type of immune cell called dendritic cells, while others believe that they come from related cells called monocytes,” said Egle Kvedaraite, MD, PhD, a physician-researcher at the Karolinska Institute and the first author of the study.

Earlier studies have shown that LCH is marked by abnormal differentiation of mononuclear phagocytes that result in inflammatory lesions with pathologic CD207+ dendritic cells (DC) harboring activating somatic MAPK (mitogen-activated protein kinase) pathway mutations. Yet, the molecular and cellular interactions that maintain the unique state of balance in LCH cells are unclear.

Scientists at the Karolinska Institute, in collaboration with Karolinska University Hospital, Singapore Immunology Network, and Newcastle University, used single-cell RNA-seq and deep-cell profiling to analyze biopsies from four pediatric LCH patients and assessed the heterogeneity of LCH granulomas by comparing LCH cells with normal mononuclear phagocytes in the lesions.

“We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance,” the authors noted.

The researchers found two main lineages of LCH cells within the lesions with dendritic cell 2 and 3 (DC2 and DC3)-like characteristics. Using high-content imaging, the researchers validated the presence of these two cell types in several LCH tissue samples. The mutated LCH cells had properties similar to both monocytes and dendritic cells, the researchers showed, as well as DC3, a relatively new type of dendritic cell.

“Today we know that DC3 has a pathway of development separate from other dendritic cells and monocytes. Knowledge of this was crucial in our study,” said Kvedaraite.

Further explorations into the molecular interactions between DC2 and DC3 using receptor-ligand analyses and in vitro lineage tracing studies showed that Notch signaling—an evolutionarily conserved cell interaction system that controls cell metabolism, proliferation, and death—enabled the two cell types to cooperate and reinforce each other during the pathological progression of LCH.

“The data suggest a dual origin model of LCH cells, linked by Notch-mediated cooperativity, and provide several new insights into the development of LCH lesions and their potential vulnerabilities to new therapeutic approaches,” the authors noted. “This phenomenon may emerge in other settings in health and disease.”

In addition to a dual origin of LCH cells, the study underscores the impact of cues from the microenvironment on the phenotype and gene expression profile of LCH cells.

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