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J Transl Med. 2018 May 21;16(1):132. doi: 10.1186/s12967-018-1508-5.

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

Xu C1, Lu X1,2, Liu W1, Chen A1, Meng G1, Zhang H1, Li B1,2, Zhang Y1, Wu J3, Wei J4,5.

Author information

1
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China.
2
The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210093, China.
3
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China. wujunhua@nju.edu.cn.
4
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China. wjw@nju.edu.cn.
5
Nanjing University Hightech Institute at Suzhou, Suzhou, 215123, China. wjw@nju.edu.cn.

Abstract

BACKGROUND:

Tumor-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.

METHODS:

The 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.

RESULTS:

FM 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.

CONCLUSIONS:

Our 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.

KEYWORDS:

Antitumor immunity; Cancer-related inflammation; Frankincense; Hepatocellular carcinoma; Myrrh; NF-κB/STAT3 signaling

PMID:
29784005
PMCID:
PMC5963062
DOI:
10.1186/s12967-018-1508-5
[Indexed for MEDLINE]
Free PMC Article

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