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2016 ; 5
(7
): e1178421
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Progressive natural killer cell dysfunction associated with alterations in subset
proportions and receptor expression in soft-tissue sarcoma patients
#MMPMID27622032
Bücklein V
; Adunka T
; Mendler AN
; Issels R
; Subklewe M
; Schmollinger JC
; Noessner E
Oncoimmunology
2016[Jul]; 5
(7
): e1178421
PMID27622032
show ga
Immunotherapy is currently investigated as treatment option in many types of
cancer. So far, results from clinical trials have demonstrated that significant
benefit from immunomodulatory therapies is restricted to patients with select
histologies. To broaden the potential use of these therapies, a deeper
understanding for mechanisms of immunosuppression in patients with cancer is
needed. Soft-tissue sarcoma (STS) presents a medical challenge with significant
mortality even after multimodal treatment. We investigated function and
immunophenotype of peripheral natural killer (NK) cells from chemotherapy-naive
STS patients (1st line) and STS patients with progression or relapse after
previous chemotherapeutic treatment (2nd line). We found NK cells from peripheral
blood of both STS patient cohorts to be dysfunctional, being unable to lyse K562
target cells while NK cells from renal cell cancer (RCC) patients did not display
attenuated lytic activity. Ex vivo stimulation of NK cells from STS patients with
interleukin-2 plus TKD restored cytotoxic function. Furthermore, altered NK cell
subset composition with reduced proportions of CD56(dim) cells could be
demonstrated, increasing from 1st- to 2nd-line patients. 2nd-line patients
additionally displayed significantly reduced expression of receptors (NKG2D),
mediators (CD3?), and effectors (perforin) of NK cell activation. In these
patients, we also detected fewer NK cells with CD57 expression, a marker for
terminally differentiated cytotoxic NK cells. Our results elucidate mechanisms of
NK cell dysfunction in STS patients with advanced disease. Markers like NKG2D,
CD3?, and perforin are candidates to characterize NK cells with effective
antitumor function for immunotherapeutic interventions.