IFN-β ACTIVATES CYTOTOXIC FUNCTION OF HUMAN NATURAL KILLER CELLS TOWARD IL-27 AND POLY(I:C) STIMULATED PC3 AND DU145 CELLS

Lymphocytes play an important role in cancer immunosurveillance. Unlike T cells, the innate lymphocytic natural killer (NK) cells do not require prior antigen sensitization to recognize and destroy abnormal cells. Instead, the activity and function of NK cells is determined by a balance of activating and inhibitory signals, which can be directed by receptor-ligand interactions and soluble mediators, such as cytokines[1]. In humans, CD3-CD56+ NK cells comprise approximately 5-10% of human peripheral blood mononuclear cells (PBMCs). Strategies that NK cells utilize to induce apoptosis in target cells include releasing cytotoxic granules containing perforin and granzymes; engaging receptors of the tumour necrosis factor (TNF) superfamily, such as Fas, TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), and TRAIL-R2 found on target cells with their corresponding ligands, FasL and TRAIL; and secreting cytokines such as TNF-α and IFN-γ[2]. These effector functions all contribute to the important role that NK cells play in targeting and eliminating cancerous cells.

In solid tumours, NK cell infiltration is generally lower and associated with poorer patient prognosis[3], [4], [5]. A recent meta-analysis revealed that NK cell infiltration is associated with a decreased risk of patient death in a variety of tumours[6]. However, even if NK cells can infiltrate the tumour, overcoming the suppressive cytokines within the microenvironment, such as IL-6[7], [8], poses another challenge. One area where harnessing NK cell-based therapies may be particularly beneficial is prostate cancer. Metastatic prostate cancer patients often face disease recurrence following first-line therapies[9], and all patients eventually die of disease[10]. It is crucial to develop a better understanding of how NK cell-based therapies can be used to treat patients with advanced prostate cancer.

Circulating NK cells in patients with prostate cancer have been shown to have impaired cytotoxic function, which worsens in patients with metastatic disease[11]. Studies suggest that activated NK cells in patients with disease is associated with a better prognosis[12], [13], [14]. These findings highlight the importance of understanding how to overcome suppression of NK cells in prostate cancer patients and how NK cells can be harnessed to effectively control tumour progression. Targeting tumour cells to manipulate their cytokine secretion profiles may be advantageous in restoring NK cell function to aid in eliminating tumour cells. For example, in the prostate tumour environment, cytokines such as TGFβ1 can contribute to suppression of NK cells by decreasing activating receptors including NKp46 and NKG2D[15].

We have previously demonstrated that interleukin (IL)-27 and Toll-like receptor (TLR)3 agonist, poly(I:C) (PIC), can alter cytokine and chemokine production from advanced prostate cancer models, PC3 and DU145 cells[16]. Additionally, IL-27 and PIC have been shown to cooperatively reduce growth of melanoma cell lines[17]. Use of the stabilized derivative of PIC, poly-ICLC, is being investigated in clinical trials for cancer patients, including those with metastatic prostate cancer[18]. It is important to understand if the addition of other agents, such as IL-27, would enhance the immune stimulating effects of this therapeutic agent. Whether IL-27 and PIC can enhance the susceptibility of PC3 and DU145 cell lines to NK cell-mediated cytotoxicity has yet to be determined.

To the best of our knowledge, this work represents the first investigation of using IL-27 and PIC to render prostate cancer cells targetable by NK cells. Our work provides insight to how altering cytokine secretion can activate NK cells to target prostate cancer cells in an interferon (IFN)-β and partially TRAIL dependent manner.

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