Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. Here we investigate the role of IL-25, an endogenous anticancer factor secreted from TAFs, in suppression of mouse 4T1 mammary tumour metastasis. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. The secretion of IL-25 from treated human or mouse fibroblasts is enhanced in vitro, and this activity confers a strong suppressive effect on growth activity of test carcinoma cells. Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel. Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities.

Dendritic cell (DC) vaccines are a newly emerging immunotherapeutic approach for the treatment and prevention of cancer, but major challenges still remain particularly with respect to clinical efficacy. Engineering and optimization of adjuvant formulations for DC-based vaccines is one strategy through which more efficacious treatments may be obtained. In this study, we developed a new ex vivo approach for DC vaccine preparation. We evaluated two highly purified mixed polysaccharide fractions from the root of Astragalus membranaceus and Codonopsis pilosulae, named Am and Cp, for their use in enhancing the efficiency of a DC-based cancer vaccine against metastasis of 4T1 mammary carcinoma in mice. Mixed lymphocyte reaction showed all Am-, Cp- and [Am+Cp]-treated DCs enhanced mouse CD4+ and CD8+ T-cell proliferation. [Am+Cp]-treated DCs exhibited the strongest anti-4T1 metastasis activity in test mice. Treatments with Am, Cp and [Am+Cp] also resulted in augmented expression of CD40, CD80 and CD86 markers in test DCs. Bioinformatics analysis of the cytokine array data from treated DCs identified that [Am+Cp] is efficacious in activation of specific immune functions via mediating the expression of cytokines/chemokines involved in the recruitment and differentiation of defined immune cells. Biochemical analysis revealed that Am and Cp are composed mainly of polysaccharides containing a high level (70–95%) glucose residues, but few or no (< 1%) mannose residues. In summary, our findings suggest that the specific plant polysaccharides Am and Cp extracted from traditional Chinese medicines can be effectively used instead of bacterial LPS as a potent adjuvant in the formulation of a DC-based vaccine for cancer immunotherapies.

Phytochemicals or their derived compounds are being increasingly recognized as potentially potent complementary treatments for cancer. Among them, some phytochemicals are being actively evaluated for use as adjuvants in anticancer therapies. For instance, shikonin and hypericin were found to induce immunogenic cell death of specific cancer cells, and this effect was able to further activate the recognition activity of tumor cells by the host immune system. On the other hand, some derivatives of phytochemicals, such as dihydrobenzofuran lignan (Q2-3) have been found to induce the secretion of an endogenous anticancer factor, namely IL-25, from non-malignant cells. These findings suggest that phytochemicals or their derivatives confer a spectrum of different pharmacological activities, which contrasts with the current cytotoxic anticancer drugs commonly used in clinics. In this review, we have collected together pertinent information from recent studies about the biochemical and cellular mechanisms through which specific phytochemicals regulate target immune systems in defined tumor microenvironments. We have further highlighted the potential application of these immunotherapeutic modifiers in cell-based cancer vaccine systems. This knowledge provides useful technological support and know how for future applications of phytochemicals in cancer immunotherapy.

Immunogenic cell death (ICD) of tumor cells occurs via various pathways that activate immune cell systems against cancer. Previous studies have demonstrated that shikonin (SK), a plant secondary metabolite, can confer strong pharmacological activities that activate ICD and strong immunogenicity of tumor cells. However, the exact hierarchical regulatory mechanisms including the molecular targets of SK-activated immunogenicity are still unknown. Here, the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was revealed to serve as a specific protein target for SK. This binding plays a key role in SK-stimulated ICD activity and the suppression of post-transcriptional mRNA processing, including nuclear export activity of newly synthesized mRNAs in mammary carcinoma cells in vitro. Moreover, it also mechanistically mediates the anti-metastatic effect of a tumor cell lysate (TCL) vaccine, which can be readily generated from SK-treated 4T1 tumor cells (SK-TCL), and the derived tumor-immunogenicity of SK-TCL-treated dendritic cells in vivo. Together, the identification of hnRNPA1 as the intracellular molecular target provides compelling pharmacology-based knowledge for the potential clinical use of SK-induced immunogenicity. In addition, SK may also serve as a potent suppressor that interferes with specific post-transcriptional activities, a mechanism which may be useful for exploitation in cancer therapeutics.

Nature Communications 7: Article number: 11311 (2016); Published: 18 April 2016; Updated: 3 June 2016 The author Yueh-Hsiung Kuo was incorrectly omitted from the list of corresponding authors in this Article. The correct information for correspondence is: ‘Correspondence and requests for materials should be addressed to Y.

This article has been corrected: An institutional investigation was conducted at the request of the Oncotarget editorial staff by the Academia Sinica Ethics Committee (Taipei, Taiwan). The Committee concluded the following: "The partial duplication of Figure 4a and 4b is judged to be a mistake during data processing, rather than a research misconduct." The correct Figure 4B is shown below; 4A appears correctly in the original article. The authors declare that these corrections do not change the results or conclusions of this paper.

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