Progressive natural killer cell dysfunction associated with alterations in subset proportions and receptor expression in soft-tissue sarcoma patients

ABSTRACT

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 (CD3ζ), 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, CD3ζ, and perforin are candidates to characterize NK cells with effective antitumor function for immunotherapeutic interventions.

KEYWORDS:

• Cancer progression
• chemotherapy
• immunotherapy
• natural killer cells
• NK cell dysfunction
• NK cell subsets
• soft-tissue sarcoma

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

AM, JCS, and EN received financial support through Deutsche Forschungsgemeinschaft (SFB-TR36) and Deutsche Krebshilfe.