Induced Pluripotent Stem Cell–conditioned Medium Suppressed Melanoma Tumorigenicity Through the Enhancement of Natural-Killer Cellular Immunity

Abstract

Induced pluripotent stem cells (iPSCs) can secrete cytokines that are involved in T-cell development and affect cytotoxic activity. To assess the effect of iPSC-conditioned medium on tumorigenicity, we retrieved splenocytes from B6 mice and cocultured them with or without irradiated B16 melanoma cells, mouse interleukin-2 (mIL-2), or iPSC-conditioned medium. Splenocyte cytotoxicity assays against B16 melanoma cells [as cytotoxic T lymphocyte (CTL) activity] and P815 cells [as natural killer (NK) activity] were performed. IL-10 and interferon-γ concentrations were measured. An in vivo subcutaneous B16 melanoma growth model was performed in B6 mice and treated with iPSC-conditioned medium. The lymphocyte subpopulation depletion test was performed to determine effectors against B16 melanoma cells. We found that unstimulated splenocytes had little cytotoxic activity. Without tumor cells, mIL-2 could augment iPSC-conditioned medium-treated CTL and NK activities (P<0.01). With irradiated tumor cells, mIL-2 treatment of splenocytes could not enhance CTL or NK activity, but iPSC-conditioned medium could enhance CTL and NK activity (P<0.001). Irradiated tumor cells induced mice splenocytes to secrete more IL-10, similar to mIL-2 treatment, but not iPSC-conditioned medium treatment. mIL-2 had better efficacy than conditioned medium in inducing splenocyte interferon-γ production. The CTL and NK cell depletion test showed that the immunostimulating effect of iPSC-conditioned medium on splenocytes was through the enhancement of NK cellular activity (P<0.05). The subcutaneous melanoma growth model showed that B16-bearing mice treated with an iPSC-conditioned medium intraperitoneal injection had a decreased tumor growth rate (P<0.01). Our study suggests that iPSC-conditioned medium had a protective effect against tumor-induced immunosuppression through the enhancement of host NK cellular activity.

Cellular Reparative Mechanisms of Mesenchymal Stem Cells for Retinal Diseases

“…In addition, Kawamura et al, 2016 further implied that the absence of host’s immune surveillance predisposed to the risk of tumorigenicity, whereby iPSC-derived cells were witnessed to form tumor in immunosuppressed allogeneic transplantation model [ 42 ]. These results were comparable to what Hsieh et al, 2016 reported in iPSC-conditioned medium [ 44 ]. It was also evident that tumor growth may be driven by pluripotent-associated genes [ 45 ].…”

Plasma Level of Circular RNA hsa_circ_0000190 Correlates with Tumor Progression and Poor Treatment Response in Advanced Lung Cancers

“…Immunotherapy through immune checkpoint inhibition by blocking the PD-1/PD-L1 signaling pathway that enhances anti-cancer T cell immunity has shown promising and significant efficacy in a variety of malignancies, including LC [ 44 , 45 , 46 , 47 ]. Clinical trials of PD-1/PD-L1 blocking antibodies demonstrated that although PD-L1 expression levels were associated with a positive response to immunotherapy, many tumors without PD-L1 expression still responded to the treatment [ 45 , 47 ].…”