Abstract
ABSTRACTA prospective analysis of natural killer (NK) cell phenotype and function was performed on fresh peripheral blood samples from untreated patients with B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Compared to healthy controls, CD56dim NK cells in CLL patients displayed reduced expression of the NKG2D activating receptor and increased CD27 expression, which indicates declines in mature cells. In addition, NK cells from CLL patients showed reduced degranulation responses toward transformed B cells alone or with rituximab and were more sensitive to activation-induced cell death. We further noted a striking reduction in the frequency and viability of NK cells expressing the inhibitory killer cell Ig-like receptors (KIR)2DL1 and/or KIR3DL1, which progressed over time in most patients. Comparisons between a CLL patient and healthy monozygotic twin were consistent with our results in the larger cohorts. Functional and biomarker alterations were less pronounced on NK cells from SLL patients, which have lower tumor burden in peripheral blood than CLL, but significant reduction in degranulation under ADCC conditions and lower frequency and viability of KIR-expressing NK cells were still evident in SLL. We conclude that mature KIR-expressing NK cells respond to the high circulating B cell tumor burden in CLL, but undergo activation-induced apoptosis. Consequently, CLL patients may benefit from therapies that augment NK cell survival and function.
Highlights
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is characterized by clonal expansion of mature B lymphocytes.[1]
We observed that high B cell counts correlated with a significant increase in numbers of natural killer (NK) cells in the blood of CLL, but not small lymphocytic lymphoma (SLL) patients, as compared with healthy donors (Fig. 1A and B)
Our data demonstrate that CLL patients undergo an expansion of NK cells in peripheral blood in parallel with increased B cell tumor burden, which is accompanied by a selective decrease in viability and loss of the NK cells that are CD56dimCD27dim/¡NKG2DbrightKIR2DL1/KIR3DL1C
Summary
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is characterized by clonal expansion of mature B lymphocytes.[1] The disease has a variable clinical course, with some patients living essentially normal lives with indolent disease for many years, while others succumb with rapidly developing complications. CLL is considered incurable by standard chemotherapy, so treatment is often withheld until disease is progressive and symptomatic.[3] Treatments vary from single alkylating agents to combinations of chemotherapy and immunotherapy, anti-CD20 monoclonal antibodies and targeted therapies affecting B cell antigen receptor signaling pathways, as well as promising chimeric antigen receptor-expressing T cells.[1] Unmet clinical needs are identifying patients who will require early therapy and tailoring therapy to disease status, including exploration of relatively non-toxic, immune-modulating therapies that could maintain the indolent phase of disease
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