CD8+ T cells mediate the antitumor activity of frankincense and myrrh in hepatocellular carcinoma

Abstract

BackgroundTumor-promoting inflammation is an emerging hallmark of cancer, which participates in both cancer progression and immune escape. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer with an extremely poor prognosis. Frankincense and myrrh are anti-inflammation agents commonly used in clinic. The purpose of this study is to investigate whether extract of frankincense and myrrh (FM) downregulates inflammatory microenvironment of HCC and thereby restores antitumor immune responses.MethodsThe water-decocting FM was obtained and quantified. HCC cell lines HCCLM3 and Hepa1-6 were used to evaluate the efficacy of FM targeting NF-κB and STAT3 signaling with western blot and qRT-PCR analysis. CD8+NKG2D+ cells were derived from human peripheral blood and were used for evaluation of immune cells-mediated inflammation and oncolysis on HCCLM3 cells. The antitumor efficacy of FM was investigated both in immune compromised and immune competent mice bearing subcutaneous HCC. Mice received daily oral gavage of FM at 60 mg/kg. Immune activity within tumor microenvironment (TME) was assessed by ELISpot assay and flow cytometry, respectively. Depletion of CD8+ T cells or NK cells was achieved by intraperitoneal injection of respective neutralizing antibody.ResultsFM significantly inhibited the activation of NF-κB and STAT3 signaling in HCC cells induced by cytokines (TNF-α or IL-6) and in co-culture system with CD8+NKG2D+ cells. Furthermore, FM sensitized HCC cells to CD8+NKG2D+ cells-mediated oncolysis. In HCC-bearing mice, FM at a non-toxic dose failed to reduce tumor growth in immune compromised mice, whereas it significantly inhibited tumor growth and prolonged life span in immune competent mice. While the number of IFN-γ-producing cells within TME was increased in mice treated with FM, the infiltration of CD8+ T cells and NK cells was not increased. Finally, we identified that depletion of CD8+ T cells rather than NK cells abrogated the antitumor activity of FM.ConclusionsOur results show for the first time that CD8+ T cells mediate the antitumor activity of FM at a non-toxic dose. This may provide new insights to this ancient mysterious prescription in cancer therapy, which offers a novel and practical therapeutic strategy and the possibilities of combined immunotherapy for HCC as well as other inflammation-related cancers in clinic.

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

“…Recently, Xu et al [75] have explored the role of pro-inflammatory response as another novel perspective in the malignant progression of tumors and the tumor immune escape. Under the inducement of frankincense and myrrh (FM), the effects of CD8 + NKG2D + T cells enriched from human peripheral blood were observed on hepatoma cell lines HCKM3 and Hepa 1-6.…”

Enhancement of Curcumin Anti-Inflammatory Effect via Formulation into Myrrh Oil-Based Nanoemulgel

“…It comprises numerous components that possess antioxidant and anti-inflammatory effects [9,10]. Likewise, myrrh oil has anticancer [11,12], analgesic [11,13] antibacterial [14], and antithrombin activities [15]. Recently, myrrh oil has been formulated as a nanoemulsion for enhancement of the antihyperlipidemic effect of atorvastatin [16].…”

Myrrh induces the apoptosis and inhibits the proliferation and migration of gastric cancer cells through down-regulating cyclooxygenase-2 expression

“…Our animal experiments verified the findings of in vitro experiments. Previous research confirmed that myrrh (or guggulsterone) has an anti-tumor effect on mice [17,41,42]. The tumor size was significantly smaller in myrrh-treated animals compared with that in the control group.…”