Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma
Graphical abstract
Introduction
Hepatocellular carcinoma (HCC) is a common and fatal cancer, with an increasing incidence worldwide.1 Though many curative therapies have been developed, the overall response to these therapies is inadequate and the long-term prognosis of patients with HCC remains poor because of its high recurrence rates.2 A lot of data have shown that tumor progression is correlated with the accumulation of myeloid-derived suppressor cells (MDSCs) which induce local and possibly systemic immunosuppression.3 Moreover, a greater prevalence of MDSCs has been correlated with early recurrence and was shown to be a predictor of poor prognosis in patients with HCC who underwent curative resection,4 radiotherapy,5 and hepatic arterial infusion chemotherapy.6 MDSCs have been shown to suppress CD8+[7], [8], [9] and CD4+ T10 cells as well as natural killer (NK)11 cells through diverse direct or indirect mechanisms.12
Cytokine-induced killer (CIK) cells are a mixed cell population of effector cells with diverse T cell receptor specificities that also possess non-major histocompatibility complex-restricted cytotoxic activity against tumor cells. CIK cells, which comprise cytotoxic T cells, NK cells, and NK-like T cells that express both NK- and T-cell markers are expanded ex vivo using recombinant IFN-γ, IL-2 and anti-CD3.13 CIK cell-based immunotherapies have been widely studied and used in the treatment of patients with cancer, including HCC.14 Currently, 90 registered clinical trials are listed on the ClinicalTrials.gov website (http://www.clinicaltrials.gov) when the following keywords are used in the search: cytokine-induced killer cells or CIK.15
A recent study determined that adjuvant immunotherapy using CIK cells appeared to reduce the recurrence of HCC and to improve overall survival.16 Although adjuvant CIK cell-based immunotherapy is a promising treatment option for early stage HCC, it lacks efficacy in advanced HCC.[17], [18], [19] We hypothesized that CIK cells could trigger a counter-regulatory immunosuppressive mechanism through recruitment of MDSCs that might hinder CIK cell antitumor activity.
We show that adoptive CIK cell therapy leads to an accumulation of MDSCs in the tumor microenvironment, which in turn suppress CIK function. We demonstrate that a PDE5 inhibitor can not only suppress MDSCs accumulation and function, but also enhance CIK cell-based therapy in murine HCC tumor models. Finally, our murine data were corroborated by human in vitro data using human CIK and tumor cells as well as MDSCs treated with a PDE5 inhibitor.
Section snippets
Cell lines
Two murine (luciferase-expressing RIL-17520 and BNL20and 2 human (Hep3B21 and PLC/PRF/521HCC cell lines were used in this study.
Drugs
Tadalafil (Selleckchem, TX, USA), a phosphodiesterase-5 (PDE5) inhibitor, was used in vitro at a concentration of 100 μM and was administered by intraperitoneal (i.p.) injection (2 mg/kg/24 h) in vivo.22 N-omega-hydroxy-L-arginine (Sigma-Aldrich, MO, USA) and N(G)-monomethyl-L-arginine (Sigma-Aldrich, MO, USA) were added to cell cultures (10 μM) in vitro.
The methods of
CIK cell therapy recruits MDSCs to tumor tissues
We tested the effect of adoptive CIK cell therapy in a murine subcutaneous HCC model using RIL-175-derived tumors. CIK cells were generated from splenocytes of tumor-free C57BL/6 mice (Fig. S1) and CIK cell therapy was initiated 2 weeks after injection of RIL-175 cells when the tumors were palpable (average tumor volume: 50 mm3). As shown in Fig. 1A, CIK cell therapy caused only marginal inhibition of subcutaneous tumor growth (p = 0.0369). We studied the tumor microenvironment by quantitative
Discussion
With the recent FDA approval of nivolumab for the treatment of patients with HCC who have been previously treated with sorafenib, immunotherapy has become a standard of care treatment option for HCC. Despite encouraging results from different clinical studies of immune checkpoint inhibitors,[28], [29] other types of immunotherapies including adoptive cell therapy remain of great interest.[30], [31] CIK cells have been shown to be active in an adjuvant setting.16 Here, we studied the
Financial support
The authors are supported by the Intramural Research Program of the NIH, NCI (ZIA-BC-011345) and a grant from the Liver Research Foundation of Korea (Bio Future Strategies Research Project).
Conflict of interest
The authors declare they have no conflicts of interest.
Please refer to the accompanying ICMJE disclosure forms for further details.
Authors’ contributions
SJ.Y, B.H., and Z.J.B. performed experiments, while SJ.Y., C.M., B.H., Z.J.B., F.K., and T.F.G. analyzed data. M.S., Q.Z., Q.F., D.A., and U.R. assisted with experiments. SJ.Y. and T.F.G. conceived and designed the project, while SJ.Y. and T.F.G. wrote the manuscript. All authors contributed to writing and all provided feedback.
Acknowledgement
We would like to thank Dr. Jung-Hwan Yoon and the Berzofsky lab for their helpful discussion.
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