Profound phenotypic deficiencies in mature blood and bone marrow progenitor dendritic cells in chronic lymphocytic...

Chronic lymphocytic leukemia (CLL) patients are immunocompromised and highly vulnerable to serious recurrent infections. Conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) are principal sensors of pathogen challenge and are essential in orchestrating innate and adaptive immune responses to resolve infection. This study identified significant deficiencies in six functionally distinct DC subsets in blood of untreated CLL (UT-CLL) patients and selective normalization of pDCs in response to acalabrutinib (a Bruton tyrosine kinase inhibitor) therapy. DCs are continuously replenished from hematopoiesis in bone marrow (BM). Four BM developmental intermediates that give rise to cDCs and pDCs were examined and significant reductions identified in UT-CLL patients supporting a precursor/progeny relationship. The deficiencies in blood DCs and BM DC progenitors were significantly associated with alterations in the Flt3/FL signaling pathway critical to DC development and function. The CLL International Prognostic Index (CLL-IPI), a highly accurate model to predict progression-free survival and time-to-first treatment (TTFT), revealed that cDC1 and pDC were reduced in High/Very High CLL-IPI compared to Low CLL-IPI patients. Notably, UT-CLL patients with shared DC subset deficiencies had shorter TTFT, uncovering a profound alteration in innate immunity with the potential to instruct therapeutic decision-making.