Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin lymphoma characterized by the expansion of malignant CD4+ T cells in the skin. There are two main subtypes of CTCL: an indolent form termed mycosis fungoides (MF), which is largely limited to the skin, and Sezary syndrome (SS), an aggressive leukemic variant of the disease which can manifest systemically.1-3 Previous studies have demonstrated defects in cell-mediated immunity in CTCL patients, including altered cytokine profiles and impaired neutrophil function, which lead to a high incidence of recurrent bacterial and viral infections as a result of decreased Th1-mediated immunity.4-9 It has also been reported that natural killer (NK)–cell function is decreased in CTCL patients,10-14 which could contribute to an overall decrease in the innate immune response to both neoplastic cells and viral or bacterial pathogens. Previous groups have reported that NK cells from SS patients are capable of responding to activation ex vivo, indicating the potential for development of immune-based therapeutics.15 Although MF patients often have a prolonged indolent clinical course of disease that requires localized treatment, there are few effective treatments for the successful management of patients with SS. Because of the lack of success with traditional chemotherapeutic approaches, novel immune-based therapeutics are being developed for use in a multitude of hematologic diseases, including CTCL.4,16-18 Understanding the immune microenvironment in patients with CTCL will be critical to the successful design of targeted therapies for their disease. Previous studies by our group and by others have shown increased expression of interleukin-15 (IL-15) in malignant CD4+ T cells in CTCL patients.19 IL-15 acts through a trimeric IL-15R complex to enhance NK-cell maturation and function.20-22 Indeed, in a first-in-human phase 1 trial in patients with refractory solid cancer tumors, IL-15 treatment induced profound expansion of circulating NK cells ({"type":"clinical-trial","attrs":{"text":"NCT01885897","term_id":"NCT01885897"}}NCT01885897).23 Considering that IL-15 is produced by malignant cells in CTCL, we sought to study the possible effect of chronically elevated IL-15 on NK-cell function in CTCL patients. In this study, we show that NK-cell activity is significantly enhanced in CTCL, and strikingly, higher NK-cell numbers are associated with increased mortality.