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Target Concepts:
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Query: EC:2.1.1.37 (
DNA methyltransferase
)
4,983
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Immunotherapies that target CD1d-restricted invariant
NKT
(iNKT) cells can prevent tumor growth in murine models but trials in humans have shown limited clinical efficacy. Here, we show that iNKT cells are depleted from blood and bronchial lavage samples from patients with non-small cell lung cancer (NSCLC) suggesting a role for these cells in immunity against NSCLC. We interrogated the Lung Cancer Explorer and Kaplan-Meier Plotter databases of NSCLC patients and found that pulmonary CD1d expression is reduced in patients with NSCLC and that low expression of CD1d mRNA is significantly associated with poor patient survival. We hypothesized that CD1d expression in NSCLC is epigenetically regulated and can be modulated using epigenetic targeting therapies. Treatment of the CD1d-negative NSCLC cell lines, A549 and SK-MES-1, with
DNA methyltransferase
inhibitors and histone deacetylase inhibitors resulted in a dose-dependent induction of CD1d mRNA and protein expression. Chromatin immunoprecipitation analysis indicated that this induction of CD1d expression directly involved chromatin remodelling. Induction of CD1d expression by A549 and SK-MES-1 cells using therapeutic low doses of
DNA methyltransferase
inhibitors and histone deacetylase inhibitors made them targets for iNKT cell-mediated cytolytic degranulation. Thus, epigenetic manipulation of CD1d expression may augment the efficacy of iNKT cell-based immunotherapies for NSCLC.
...
PMID:Epigenetic induction of CD1d expression primes lung cancer cells for killing by invariant natural killer T cells. 2987 51
Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Ovarian cancer has thus far been refractory to immunotherapies that stimulate the host immune system to recognize and kill cancer cells. This may be because of a suppressive tumor immune microenvironment and lack of recruitment and activation of immune cells that kill cancer cells. Our previous work showed that epigenetic drugs including
DNA methyltransferase
inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. We find that combining DNMTi and HDAC6i results in an amplified type I interferon response, leading to increased cytokine and chemokine expression and higher expression of the MHC I antigen presentation complex in human and mouse ovarian cancer cell lines. Treating mice bearing ID8 Trp53-/- ovarian cancer with HDAC6i/DNMTi led to an increase in tumor-killing cells such as IFNg+ CD8, NK, and
NKT
cells and a reversal of the immunosuppressive tumor microenvironment with a decrease in MDSCs and PD-1
hi
CD4 T cells, corresponding with an increase in survival. Thus combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment.
...
PMID:Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer. 3210 5
