The capacity of natural killer (NK) cells to kill tumor cells without specific antigen recognition provides an advantage over T cells and makes them potential effectors for tumor immunotherapy. However, the efficacy of NK cell adoptive therapy can be limited by the immunosuppressive tumor microenvironment. Transforming growth factor-β (TGF-β) is a potent immunosuppressive cytokine that can suppress NK cell function. To convert the suppressive signal induced by TGF-β to an activating signal, we genetically modified NK-92 cells to express a chimeric receptor with TGF-β type II receptor extracellular and transmembrane domains and the intracellular domain of NK cell-activating receptor NKG2D (TN chimeric receptor). NK-92 cells expressing TN receptors were resistant to TGF-β-induced suppressive signaling and did not down-regulate NKG2D. These modified NK-92 cells had higher killing capacity and interferon γ (IFN-γ) production against tumor cells compared with the control cells and their cytotoxicity could be further enhanced by TGF-β. More interestingly, the NK-92 cells expressing TN receptors were better chemo-attracted to the tumor cells expressing TGF-β. The presence of these modified NK-92 cells significantly inhibited the differentiation of human naïve CD4 T cells to regulatory T cells. NK-92-TN cells could also inhibit tumor growth in vivo in a hepatocellular carcinoma xenograft tumor model. Therefore, TN chimeric receptors can be a novel strategy to augment anti-tumor efficacy in NK cell adoptive therapy.

Background Innate lymphoid cells (ILCs) are a newly discovered family of immune cells that have similar cytokine-secreting profiles as T helper cell subsets. Although ILCs are critical for host defense against infections and tissue homeostasis, their roles in tumor development are not well established. Methods We studied the function of ILC3 cells in the liver for the development of hepatocellular carcinoma (HCC) in murine HCC models using flow cytometry, adoptive transfer, and in vitro functional assays. Findings We found that ILC3 lacking the natural cytotoxicity-triggering receptor (NCR − ILC3) promoted the development of HCC in response to interleukin 23 (IL-23). IL-23 serum level is elevated in HCC patients and its high expression is associated with poor clinical outcomes. We found that IL-23 could promote tumor development in murine HCC tumor models. IL-23 promoted the expansion of NCR − ILC3 and its differentiation from group 1 ILCs (ILC1s). Furthermore, NCR − ILC3 initiated IL-17 production upon IL-23 stimulation and directly inhibited CD8 + T cell immunity by promoting lymphocyte apoptosis and limiting their proliferation. Interpretation Together, our findings suggest that NCR − ILC3 initiates the IL-17-rich immunosuppressive tumor microenvironment and promotes the development of HCC, thus may serve as a promising target for future cancer immunotherapy. Fund This work was supported by grants from National Natural Science Foundation of China (81471586, 81571556), the Priority Academic Program Development of Jiangsu Higher Education Institutions, the collaborative Innovation Center of Hematology, start-up grant from National University of Singapore, the Cancer Prevention and Research Institute of Texas CPRIT (RR180017), and the National Cancer Institute's Cancer Center Support (Core) Grant CA016672 (to The University of Texas MD Anderson Cancer Center).

IL-35 is a newly discovered inhibitory cytokine secreted by regulatory T cells (Tregs) and may have therapeutic potential in several inflammatory disorders. Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation and caused by donor T cells and inflammatory cytokines. The role of IL-35 in aGVHD is still unknown. Here we demonstrate that IL-35 overexpression suppresses CD4+ effector T cell activation, leading to a reduction in alloreactive T-cell responses and aGVHD severity. It also leads to the expansion of CD4+Foxp3+ Tregs in the aGVHD target organs. Furthermore, IL-35 overexpression results in a selective decrease in the frequency of Th1 cells and an increase of IL-10-producing CD4+ T cells in aGVHD target tissues. Serum levels of TNF-α, IFN-γ, IL-6, IL-22 and IL-23 decrease and IL-10 increases in response to IL-35. Most importantly, IL-35 preserves graft versus leukemia effect. Finally, aGVHD grade 2-4 patients have decreased serum IL-35 levels comparing with time-matched patients with aGVHD grade 0-1. Our findings indicate that IL-35 plays an important role in reducing aGVHD through promoting the expansion of Tregs and repressing Th1 responses, and should be investigated as the therapeutic strategy for aGVHD.

No abstract

IL-33 released by epithelial cells and immune cells functions as an alarmin and can induce both type 1 and type 2 immune responses. However, the role of IL-33 release in tumor development is still not clear. In this study, we examined the function of released IL-33 in murine hepatocellular carcinoma (HCC) models by hydrodynamically injecting either IL-33–expressing tumor cells or IL-33–expressing plasmids into the liver of tumor-bearing mice. Tumor growth was greatly inhibited by IL-33 release. This antitumor effect of IL-33 was dependent on suppression of tumorigenicity 2 (ST2) because it was diminished in ST2−/− mice. Moreover, HCC patients with high IL-33 expression have prolonged overall survival compared with the patients with low IL-33 expression. Further study showed that there were increased percentages and numbers of activated and effector CD4+ and CD8+ T cells in both spleen and liver in IL-33–expressing tumor-bearing mice. Moreover, IFN-γ production of the CD4+ and CD8+ T cells was upregulated in both spleen and liver by IL-33. The cytotoxicity of CTLs from IL-33–expressing mice was also enhanced. In vitro rIL-33 treatment could preferentially expand CD8+ T cells and promote CD4+ and CD8+ T cell activation and IFN-γ production. Depletion of CD4+ and CD8+ T cells diminished the antitumor activity of IL-33, suggesting that the antitumor function of released IL-33 was mediated by both CD4+ and CD8+ T cells. Taken together, we demonstrated in murine HCC models that IL-33 release could inhibit tumor development through its interaction with ST2 to promote antitumor CD4+ and CD8+ T cell responses.