Epigenetics is a study of modulation of gene function through non-heritable mechanisms such as histone modification and DNA methylation. These mechanisms are so potent that observed phenotypes could be mistaken for genomic mutations. In clinics, epigenetics plays especially important role during therapeutic treatment where drug effectiveness varies widely among pool of patients, for example, during immunotherapy in cancer patients.
For example, a new paper recently in Nature showed that both (a) EZH2-mediated histone H3 lysine 27 trimethylation (H3K27me3) and (b) DNA methyltransferase 1-mediated DNA methylation independently silence cancer cells' responsiveness to IFN-γ/T cells and their activity inversely correlated with patients outcome.
The authors have used EZH2 inhibitor GSK126 or DNMT1 inhibitor 5-AZA-dC. Using humanized mouse model of ovarian cancer, the authors showed that combination of GSK126 and 5-AZA-dC synergized with tumor-specific T cells in tumor protection (inhibitors alone or in absence of T cells had no/minimal effect).
Interestingly, combination of GSK126 and 5-AZA-dC specifically enhanced tumor expression of Th1 chemokines CXCL9 and CXCL10 in response to IFN-γ.
Further experiments showed that both inhibitors could independently enhanced cancer CXCL10 expression in response to IFN-γ (here, primary ovarian cancer cells were pre-treated with shEZH2 or shDNMT and exposed to 5-AZA-dC and GSK126 respectively).
As an additional control, the authors showed that GSK126 had no effect on DNMT1 and 5-AZA-dC had no effect on H3K27me3.
Finally, the authors found negative correlation between expression level of EZH2 and DNMT1 and cancer patients survival.
In summary, this study expands our understanding of cancer tissue sensitivity to immunotherapy (including to anti-PD1 therapy). It appears that in some patients EZH2 and DNMT1 selectively silence TH1 chemokine locus and inhibit cancer cell responsiveness to IFN-γ derived from tumor infiltrated T cells thus blocking positive loop for attracting and recruiting additional tumor-specific T cells. Accordingly, application of selective inhibitors of EZH2 and DNMT1 could improve cancer patients survival.
Of note: it is not clear why would cancer cells silence only Th1 chemokine locus. While it is true that Th1 play important role in cancer protection, several other cancer models have shown protective role for Th17 and even Th2 cells. Since we don't know whether cancer protection in this paper is dependent of IFN-γ, we have no way to make any conclusion in this matter.
David Usharauli
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