NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors

ABSTRACT

A 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, CD56^dim 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.

Keywords:

• Chronic lymphocytic leukemia (CLL)
• killer cell Ig-like receptors (KIR)
• natural killer (NK) cells
• small lymphocytic lymphoma (SLL)

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank JoEllen Weaver, Mary Gilroy, Barbara Dettore, Loretha Moore, and Ryan Winters from the FCCC Biosample Repository for coordinating patient consenting and donations, Drs. Richard Hardy, Poliana Patah, and Valentin Robu for advice, and support from the FCCC Cell Culture, Genomics, Flow Cytometry, and Biostatistics & Bioinformatics Facilities. This manuscript is dedicated to the memory of Dr. Elena Gitelson, who inspired our successful search for a patient with a healthy identical twin.

Funding

This work was supported by the FCCC Keystone Program in Blood Cell Development and Cancer, the Main Line and Bucks County Board of Associates, the National Institutes of Health under Grants CA083859 (K.S.C.) and CA06927 (FCCC), and a Health Research Formula Fund (CURE) grant from the PA Department of Health (K.S.C.).