Biological effects of IL-21 on immune cells and its potential for cancer treatment.

Interleukin-21 (IL-21), a member of the IL-2 cytokine family, is one of the most important effector and messenger molecules in the immune system. Produced by various immune cells, IL-21 has pleiotropic effects on innate and adaptive immune responses via regulation of natural killer, T, and B cells. An anti-tumor role of IL-21 has also been reported in the literature, as it may support cell proliferation or on the contrary induce growth arrest or apoptosis of the tumor cell. Anti-tumor effect of IL-21 enhances when combined with other agents that target tumor cells, immune regulatory circuits, or other immune-enhancing molecules. Therefore, understanding the biology of IL-21 in the tumor microenvironment (TME) and reducing its systemic toxic and side effects is crucial to ensure the maximum benefits of anti-tumor treatment strategies. In this review, we provide a comprehensive overview on the biological functions, roles in tumors, and the recent advances in preclinical and clinical research of IL-21 in tumor immunotherapy.

Expression of the Inhibitory Receptor TIGIT Is Up-Regulated Specifically on NK Cells With CD226 Activating Receptor From HIV-Infected Individuals.

Natural killer (NK) cells are important for maintenance of innate immune system stability and serve as a first line of defense against tumors and virus infections; they can act either directly or indirectly and are regulated via co-operation between inhibitory and stimulatory surface receptors. The recently reported inhibitory receptor, TIGIT, can be expressed on the NK cell surface; however, the expression level and function of TIGIT on NK cells during HIV infection is unknown. In this study, for the first time, we investigated the expression and function of TIGIT in NK cells from HIV-infected individuals. Our data demonstrate that the level of TIGIT is higher on NK cells from patients infected with human immunodeficiency virus (HIV) compared with HIV-negative healthy controls. TIGIT expression is inversely correlated with CD4+ T cell counts and positively correlated with plasma viral loads. Additionally, levels of the TIGIT ligand, CD155, were higher on CD4+ T cells from HIV-infected individuals compared with those from healthy controls; however, there was no difference in the level of the activating receptor, CD226, which recognizes the same ligands as TIGIT. Furthermore, TIGIT was found to specifically up-regulated on CD226+ NK cells in HIV-infected individuals, and either rIL-10, or rIL-12 + rIL-15, could induce TIGIT expression on these cells. In addition, high TIGIT expression inhibited the production of interferon-gamma (IFN-γ) by NK cells, while TIGIT inhibition restored IFN-γ production. Overall, these results highlight the important role of TIGIT in NK cell function and suggest a potential new avenue for the development of therapeutic strategies toward a functional cure for HIV.

IL-10+ NK and TGF-ß+ NK cells play negative regulatory roles in HIV infection.

BACKGROUND: Natural killer (NK) cells play cytotoxic roles by targeting tumor cells or virus infected cells, they also play regulatory roles by secreting cytokines and chemokines. Transforming growth factor (TGF)-ß and interleukin (IL)-10 are important immunosuppressive cytokines potentially related to the immune dysregulation that occurs in the infection of human immunodeficiency virus (HIV). NK cells are an important source of TGF-ß and a main early producer of IL-10 in response to viral infection. Here, we evaluated the percentages of IL-10+ and TGF-ß+ NK cells in HIV-infected patients relative to healthy controls (HCs). METHODS: Study participants (n = 63) included 31 antiretroviral treatment (ART)-naïve HIV-infected patients, 17 ART-treated HIV-infected patients, and 15 HIV-negative HCs. Expression of IL-10 or TGF-ß in NK cells was examined by flow cytometry, and the influences of recombinant IL-10 (rIL-10) or recombinant TGF-ß (rTGF-ß) on NK cell function were investigated in vitro. RESULTS: Compared with HCs, ART-naïve HIV-infected patients had increased percentages of IL-10+ (2.0% vs. 0.4%, p = 0.015) and TGF-ß+ (4.5% vs. 2.1%, p = 0.022) NK cells, and ART-treated patients also had a higher percentage of IL-10+ NK cells (2.5% vs. 0.4%, p = 0.002). The percentages of IL-10+ and TGF-ß+ NK cells were positively correlated (r = 0.388; p = 0.010). The results of in vitro experiments demonstrated that rIL-10 and rTGF-ß inhibited NK cell CD107a expression (p = 0.037 and p = 0.024, respectively), IFN-γ secretion (p = 0.006, p = 0.016, respectively), and granzyme B release after stimulation (p = 0.014, p = 0.040, respectively). CONCLUSIONS: Our data suggest that the percentages of IL-10+ or TGF-ß+ NK cells are increased in HIV-infected patients, and that rIL-10 and/or rTGF-ß can inhibit NK cell functions in vitro, providing a potential therapeutic target for strategies aimed at combating HIV infection.

Elevated interferon-γ-induced protein 10 and its receptor CXCR3 impair NK cell function during HIV infection.

As the first line of defense in the human immune system, NK cells play essential roles in prevention of tumorigenesis and viral infection. It is known that NK cells have impaired function in HIV infection; however, it remains unclear why this occurs. IP-10 is a chemokine and inflammatory factor that is associated with such diseases as tuberculosis, hepatitis B virus, and pancreatic cancer. The aim of this study was to evaluate IP-10 levels and CXCR3 expression in NK cells that were affected by HIV and to elucidate whether NK cell function could be affected by IP-10. Our results demonstrate that IP-10 levels and expression of CXCR3 in NK cells was significantly higher in HIV-infected participants compared with noninfected participants. Moreover, the ability of NK cells to secrete IFN-γ and, specifically, to lyse K562, was suppressed with exposure to high levels of IP-10. This study also showed that CXCR3+ NK cell function decreased dramatically when treated with IP-10, which indicates that CXCR3+ NK cells were the main targets of IP-10. Furthermore, IP-10 or CXCR3 blocking could restore NK cell function. These data suggest that elevated IP-10 levels may impair NK cell function during HIV infection and that IP-10/CXCR3 blocking may be a novel therapeutic strategy in the control and functional cure of HIV.