IL15 induces a potent antitumor activity in NK cells isolated from malignant pleural effusions and overcomes the inhibitory effect of pleural fluid

Abstract

Natural Killer (NK) cells are capable of recognizing and killing cancer cells and play an important role in tumor immunosurveillance. However, tumor-infiltrating NK cells are frequently impaired in their functional capability. A remarkable exception is represented by NK cells isolated from malignant pleural effusions (PE) that are not anergic and, upon IL2-induced activation, efficiently kill tumor cells. Although IL2 is used in various clinical trials, severe side effects may occur in treated patients. In this study, we investigated whether also other clinical-grade cytokines could induce strong cytotoxicity in NK cells isolated from pleural fluid of patients with primary or metastatic tumors of different origins. We show that PE-NK cells, cultured for short-time intervals with IL15, maintain the CD56 phenotype, a high expression of the main activating receptors, produce cytokines and kill tumor cells similarly to those treated with IL2. Moreover, IL15-activated PE-NK cells could greatly reduce the growth of established tumors in mice. This antitumor effect correlated with the ability of IL15-activated PE-NK cells to traffic from periphery to the tumor site. Finally, we show that IL15 can counteract the inhibitory effect of the tumor pleural microenvironment. Our study suggests that IL15-activated NK cells isolated from pleural fluid (otherwise discarded after thoracentesis) may represent a suitable source of effector cells to be used in adoptive immunotherapy of cancer.

Presence of innate lymphoid cells in pleural effusions of primary and metastatic tumors: Functional analysis and expression of PD‐1 receptor

“…Recently, NK cells have been found in mPE of primary and metastatic pleural tumors. Notably, mPE‐NK cells could kill tumor cells even more efficiently than autologous peripheral blood NK cells, upon short time culture in IL‐15 or IL‐2 . On the other hand, the possible effect of helper ILC1/2/3, on either tumor control or progression is poorly known.…”

“…In this context, ILC3 have been shown to support the formation of TA‐TLS that favor the capture and the presentation of tumor antigens to T lymphocytes and the initiation of tumor‐specific immune responses . In a previous study, we showed that NK cells present in malignant pleural effusions (mPE) are not anergic, as they can release cytokines, and kill efficiently tumor targets including autologous tumor cells . However, no information is available on the actual presence and on the possible effect of other ILC subsets in mPE derived from patients with primary or metastatic tumors.…”

Exploiting Human NK Cells in Tumor Therapy

“…Thus, primary strategies in immunotherapy are aimed to boost in vivo NK cell-mediated antitumor activity. One approach is based on the in vivo administration of cytokines, such as IL-2 and IL-15, that determine NK cell activation, differentiation, and expansion (8,(28)(29)(30)(31)(32). IL-2 administration was approved in the 1990s for the treatment of metastatic RCC 2.…”

“…For example, the pleural fluid of primary or metastatic tumors contains high numbers of functional NK cells (19), which acquire strong cytotoxicity upon short culture intervals with IL-15 or IL-2 in vitro. Since large volumes of such fluids are routinely discarded, NK cells could be recovered and reinfused systemically or in the pleural cavity after in vitro culture with IL-15 (8). Such loco-regional treatment might contribute to the control of pleural localizations of the tumor.…”

Progression or suppression: Two sides of the innate lymphoid cells in cancer

“…The tumor microenvironment includes nonmalignant cells such as endothelial cells, macrophages, fibroblasts, mesenchymal stromal cells and other myeloid cells; and nonmalignant tumor-associated (TA) cells and tumor cells with their inhibitory activity cytokine and soluble factors. [61][62][63][64][65] Besides this, the tumor microenvironment is a permissive medium for microbial growth as it harbors oxygen and nutritional niches. 66 The tumor microenvironment regulates tumor tissue development.…”