Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy.

Loss-of-function mutations in genes encoding TET DNA dioxygenase occur frequently in hematopoietic malignancy, but rarely in solid tumors which instead commonly have reduced activity. The impact of decreased TET activity in solid tumors is not known. Here we show that TET2 mediates interferon γ (IFNγ)-JAK-STAT signaling pathway to control chemokine and PD-L1 expression, lymphocyte infiltration and cancer immunity. IFNγ stimulated STAT1 to bind TET2 and recruit TET2 to hydroxymethylate chemokine and PD-L1 genes. Reduced TET activity was associated with decreased TH1-type chemokines and tumor-infiltrating lymphocytes (TILs) and the progression of human colon cancer. Deletion of Tet2 in murine melanoma and colon tumor cells reduced chemokine expression and TILs, enabling tumors to evade anti-tumor immunity and to resist anti-PD-L1 therapy. Conversely, stimulating TET activity by systematic injection of its co-factor, ascorbate/vitamin C, increased chemokine and TILs, leading to enhanced anti-tumor immunity and anti-PD-L1 efficacy and extended lifespan of tumor-bearing mice. These results suggest an IFNγ-JAK-STAT-TET signaling pathway that mediates tumor response to anti-PD-L1/PD-1 therapy and is frequently disrupted in solid tumors. Our findings also suggest TET activity as a biomarker for predicting the efficacy and patient response to anti-PD-1/PD-L1 therapy, and stimulating TET activity as an adjuvant immunotherapy of solid tumors.

Total sesquiterpene lactones isolated from Inula helenium L. attenuates 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in mice.

BACKGROUND: Inula helenium L. is an herb whose anti-inflammatory properties are attributed to its active components, the sesquiterpene lactones (SLs). Our previous study demonstrated that the total sesquiterpene lactones isolated from Inula helenium L. (TSL-IHL), consisting mainly of alantolactone (AL) and isoalantolactone (IAL), may have potential in the prevention and treatment of rheumatoid arthritis (RA). However, the effect of TSL-IHL on atopic dermatitis (AD) has not been studied yet. AIM OF THE STUDY: The present study evaluates the potential of TSL-IHL as a treatment for AD. METHODS/STUDY DESIGNS: The effects of TSL-IHL on the expression of inflammatory genes and the activation of NF-κB signaling pathway in HaCat cells were examined by quantitative real-time PCR and western blotting, respectively, and compared with those of AL and IAL. The protective effect of TSL-IHL against AD was tested in a mouse model induced by 2,4-dinitrochlorobenzene (DNCB), in which AD-like skin lesions were induced in ICR mice by sensitizing once with 100 µl of 7% DNCB painted on their shaved back skin and then challenging with 20 µl of 0.2% DNCB five times on their right ears at 3 day intervals starting on day 5 post-sensitization. RESULTS: TSL-IHL, as well as AL and IAL, could all inhibit TNF-α-induced activation of NF-κB and the expression of TNF-α, IL-1, and IL-4 in HaCat cells in a dose-dependent manner in the range of 0.6-2.4 µg/ml. The topical application of TSL-IHL (1% W/W in emollient cream) attenuated DNCB-induced dermatitis severity and right ear swelling. The serum levels of IgE, TNF-α and IFN-γ in TSL-IHL-treated mice were reduced by 81.39%, 89.69%, and 87.85%, respectively, while the mRNA levels of IL-4, IL-5 and IL-13, in the back-skin lesions of TSL-IHL-treated mice were reduced by 39.21%, 40.62% and 48.12%, respectively, compared with the untreated controls. Histopathological examination showed that TSL-IHL treatment reduced epidermis/dermis thickening and dermal inflammatory infiltration in both ear and back skins. CONCLUSIONS: We suggest that TSL-IHL inhibited the development of AD-like skin symptoms by regulating cytokine expression and may be an effective alternative therapy for AD.

Inhibition effects of all trans-retinoic acid on the growth and angiogenesis of esophageal squamous cell carcinoma in nude mice.

BACKGROUND: The potential application of retinoic acid receptor activators, such as all trans-retinoic acid (ATRA), for treating various cancers have been studied both pre-clinically and clinically. Whether ATRA has an anticancer effect on human esophageal squamous cancer cell (ESCC) is still unknown. We have explored the anticancer effect of ATRA in ESCC, and in this study, the effects of ATRA on levels and patterns of expression of the vascular endothelial growth factor (VEGF) signal transduction pathway in transplantable tumor growth of the human ESCC cell line, EC9706, in nude mice. METHODS: The animal model of the ESCC xenograft was made by subcutaneous implantation of tumor cells into nude mice. Reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemical assays were used to detect the expression of the VEGF signal transduction pathway in ESCC xenograft tissues. RESULTS: Compared to the control group, the tumor inhibition rates in the low dose ATRA, high dose ATRA, and 5-FU groups were 83.21%, 88.32%, 91.02%, respectively. The protein and mRNA levels of VEGF were down-regulated after being treated with ATRA and 5-FU compared to the control group (P < 0.05). The study also revealed that ATRA specifically down-regulated VEGF and the component of the VEGF signal transduction pathway of CD31, CD34, and CD105 (component of the TGF-ß receptor) in ESCC xenograft tissues (P < 0.05). CONCLUSIONS: ATRA can significantly inhibit tumor growth and has anticancer effects on transplantable tumor growth of human ESCC cell line EC9706 in nude mice. These findings indicate that ATRA specifically down regulated VEGF and the components of VEGF signal transduction, which may be an important mechanism responsible for the neoangiogenesis inhibition of ESCC cells.