Immuno-regulatory malignant B cells contribute to Chronic Lymphocytic Leukemia progression.
Arsène MékinianAnne QuinquenelKoceïla Ait BelkacemFeriel KanounElisabetta DondiEmilie FranckMarouane BoubayaMaïssa MhibikFanny Baran-MarszakRémi LetestuFlorence Ajchenbaum-CymbalistaVincent LévyNadine Varin-BlankChristine Le RoyPublished in: Cancer gene therapy (2023)
Chronic Lymphocytic Leukemia (CLL) is a heterogeneous B cell neoplasm ranging from indolent to rapidly progressive disease. Leukemic cell subsets with regulatory properties evade immune clearance; however, the contribution of such subsets during CLL progression is not completely elucidated. Here, we report that CLL B cells crosstalk with their immune counterparts, notably by promoting the regulatory T (Treg) cell compartment and shaping several helper T (Th) subsets. Among various constitutively- and BCR/CD40-mediated factors secreted, tumour subsets co-express two important immunoregulatory cytokines, IL10 and TGFβ1, both associated with a memory B cell phenotype. Neutralizing secreted IL10 or inhibiting the TGFβ signalling pathway demonstrated that these cytokines are mainly involved in Th- and Treg differentiation/maintenance. In line with the regulatory subsets, we also demonstrated that a CLL B cell population expresses FOXP3, a marker of regulatory T cells. Analysis of IL10, TGFβ1 and FOXP3 positive subpopulations frequencies in CLL samples discriminated 2 clusters of untreated CLL patients that were significantly different in Tregs frequency and time-to-treatment. Since this distinction was pertinent to disease progression, the regulatory profiling provides a new rationale for patient stratification and sheds light on immune dysfunction in CLL.
Keyphrases
- chronic lymphocytic leukemia
- regulatory t cells
- transcription factor
- peripheral blood
- dendritic cells
- transforming growth factor
- single cell
- end stage renal disease
- newly diagnosed
- clinical trial
- multiple sclerosis
- peritoneal dialysis
- oxidative stress
- low grade
- chronic kidney disease
- case report
- working memory
- tyrosine kinase
- mesenchymal stem cells
- replacement therapy
- smoking cessation