Few days ago I reviewed new Nature article where the authors found a negative correlation between EZH2hi tumor phenotype (EZH2 is a methyltransferase involved in epigenetic modification at H3K27me3) and progression-free survival of ovarian cancer patients.
Now, it appears that the same group had another paper in Nature immunology showing exactly opposite effect of EZH2 in tumor infiltrating CD8 T cells (TIL). Namely, the authors found a positive correlation between frequency of EZH2-positive CD8 TILs and progression-free survival of ovarian cancer patients.
First, the authors showed that in human CD8 T cells, EZH2+ subset displayed increased polyfunctionality.
Indeed, inhibition of EZH2 by GSK126 in in vitro CD8 T cells reduced their polyfunctionality.
Next, the authors found that, like GSK126, tumor tissue environment suppressed EZH2 level and TIL functionality by reducing access to glucose.
In another set of experiments, the authors showed that adoptive transfer of EZH2 inhibitor (drug or shRNA) pre-treated tumor-specific CD8 T cells failed to control melanoma metastases in lung.
Finally, analysis of clinical samples from ovarian cancer patients revealed positive correlation between frequency of EZH2+CD8+ subset and disease-free survival.
In summary, this paper indicates that glucose deprivation in tumor environment reduces EZH2 expression in TIL CD8 T cells and reduces their functionality, implying that increasing of EZH2 expression would benefit cancer patients.
Now these results are exactly opposite from the results provided in Nature paper. There, EZH2 expression in tumor cells inhibited TIL infiltration and EZH2hi tumor phenotype showed reduced progression-free survival in ovarian cancer patients implying that decreasing of EZH2 expression would benefit cancer patients.
The only difference between these two papers is that one mostly deals with cancer cells and another with CD8 T cells. But this separation in vivo is hardly feasible suggesting more difficult path for medical application of discoveries in epigenetics [it is not clear how the same tumor environment reduces EZH2 expression in TIL CD8 T cells and at the same time increasing it in cancer cells].
David Usharauli
Indeed, inhibition of EZH2 by GSK126 in in vitro CD8 T cells reduced their polyfunctionality.
Next, the authors found that, like GSK126, tumor tissue environment suppressed EZH2 level and TIL functionality by reducing access to glucose.
In another set of experiments, the authors showed that adoptive transfer of EZH2 inhibitor (drug or shRNA) pre-treated tumor-specific CD8 T cells failed to control melanoma metastases in lung.
Finally, analysis of clinical samples from ovarian cancer patients revealed positive correlation between frequency of EZH2+CD8+ subset and disease-free survival.
In summary, this paper indicates that glucose deprivation in tumor environment reduces EZH2 expression in TIL CD8 T cells and reduces their functionality, implying that increasing of EZH2 expression would benefit cancer patients.
Now these results are exactly opposite from the results provided in Nature paper. There, EZH2 expression in tumor cells inhibited TIL infiltration and EZH2hi tumor phenotype showed reduced progression-free survival in ovarian cancer patients implying that decreasing of EZH2 expression would benefit cancer patients.
The only difference between these two papers is that one mostly deals with cancer cells and another with CD8 T cells. But this separation in vivo is hardly feasible suggesting more difficult path for medical application of discoveries in epigenetics [it is not clear how the same tumor environment reduces EZH2 expression in TIL CD8 T cells and at the same time increasing it in cancer cells].
David Usharauli
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