Therapeutic Targeting of Immune Dysfunction in Langerhans Cell Histiocytosis
Abstract
Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder with similar incidence and overall survival as pediatric Hodgkins Lymphoma. The current therapeutic standard of care for patients with multi-focal disease remains empiric chemotherapy which fails in over 50% of patients, and treatment failure is associated with significant long-term morbidity and mortality. Translational research resources and efforts to study LCH have been relatively sparse due to challenging samples and the lack of reliable pre-clinical models. To address this issue the Histiocytosis Program at Texas Childrens Cancer Center has developed an unprecedented research resource of ~1000 viably preserved LCH lesions and paired peripheral blood mononuclear cells, along with associated clinical data. In addition, we generated the first mouse models of LCH-like disease, allowing us to characterize the molecular mechanisms that drive LCH. LCH lesions histology reveals a universal feature of accumulation of Langerin-positive dendritic cells along with a large inflammatory infiltrate. Upon immune cell phenotyping of LCH microenvironment we found T lymphocytes are most abundant but are dysfunctional and express exhaustion markers on their surface. To improve outcomes for patients, we not only need to more completely define the mechanisms driving LCH, but also to translate these discoveries into improved therapeutic strategies. The objective of this proposal is to develop pre-clinical models to determine the most effective therapeutic strategies for patients with LCH. We hypothesize that combination therapeutic strategies targeting MAPK activation and dysfunctional T cells can overcome the immune suppressive microenvironment in LCH, leading to better clinical outcomes than chemotherapy or MAPK inhibition alone.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2021
- Accession Number
- AD1169008
Entities
People
- Rikhia C. Chakraborty
Organizations
- Baylor College of Medicine