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Peixoto et al. Cancer Drug Resist 2018;1:219-29 I http://dx.doi.org/10.20517/cdr.2018.17 Page 225

MDSCs suggesting that targeting only one epigenetic enzyme may lead to opposite results although
molecular mechanisms remain unknown.

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Many previous studies demonstrated the central role of epigenetic modifications on CD4 T-cell polarization
and therefore on cancer prognosis and outcome. Indeed, while Th1 polarization is associated with a good
+
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prognosis, Tregs (CD4 , FOXP3 ) are immunoregulators whose presence in the tumor immune infiltrate is
+
associated with a repression of CD8 T-cells and NKs activity via the production of IL-10, IL-35 and TGFβ.
[52]
Epigenetic drugs might also activate FOXP3 expression and immunotolerance and thus might limit the
benefits of immunotherapy. However, it has been recently reported, in the breast cancer 4T1 and in NSCLC
cells, that the use of large spectra HDACi or Mocetinostat increased PD-L1 expression and conconmitantly
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down-regulate T-regs leading to increased CD8 T-cell infiltration and survival in mice suggesting that Tregs
might also be inhibited by epidrugs [50,51] .
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Cytosolic NADP -dependent isocitrate dehydrogenase 1 and glioma
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LGGs associated with a wild type cytosolic NADP -dependent isocitrate dehydrogenase 1 (IDH1) gene,
present a very aggressive phenotype which is comparable to the high grade glioma glioblastoma (GBM).
Moreover, the tumors with a non-mutated IDH1 locus present a more immunosuppressive context, than
those carrying a mutated IDH1 gene, and expressed higher levels of PD-L1 correlated to a lower level of PD-
L1 promoter methylation than the one observed in the tumors with the mutated form of the gene [32,53,54] .
These data could be explained by the fact that the mutated IDH1 protein produces higher levels of
2-hydroxyglutarate, a specific sub-product which favors methylation and repression of the PD-L1 promoter.
Altogether, these data suggest that some specific subtypes of LGGs may respond differently to anti-
checkpoint inhibitor therapies. We could then speculate that the use of anti-PD-L1 immunotherapies may
improve conventional treatment outcomes when used in patients diagnosed with a LGG carrying a non-
mutated IDH1 gene but not in tumors carrying the mutated version of the gene. For these last patients, these
treatments should be combined with DNA demethylating agents. In addition, expression of PD-L1 mRNA
in GBM has also been associated with non-mutated IDH1 gene and poor prognosis suggesting that overall
survival of these patients could be significantly improved by anti-PD-L1 therapies .
[55]

Clinical trials
Interestingly, therapy resistance linked to demethylating agents which are used in several first line anti-
cancer therapies and which induce the expression of PD-L1 could be annihilated in the second line of
treatment by an anti-PD-L1 strategy. Phase I/II clinical trials including patients with different cancer origins
(NSCLC, diffuse large B-cell lymphoma, metastatic or normal breast cancer, melanoma, squamous cell
carcinoma of the oral cavity, colorectal cancer, HNSCC, renal carcinoma, urothelial carcinoma, lymphoma,
leukemia, ovarian carcinoma, MDS) and treated with demethylating agents (5-Aza or 5-AzaCdR) or HDACi
[56]
(vorinostat or entinostat) combined with ICB therapy are currently in progress and summarized in .
For example, the NCT02961101 phase1/2 trial is recruiting patients to analyze the effects of a treatment
combining a low dose of decitabine with anti-PD-1 in relapsed or refractory malignancies in cancer of
different origins.

PROMISING NEW COMBINATIONS OF EPIDRUGS WITH ANTI-PD-1/PD-L1
Numerous clinical trials showed a large resistance to anti-PD-1 treatment in TNBC and these data were
confirmed in mouse models since anti-PD-1 antibodies also failed to produce an objective response in
[57]
TNBC xenograph models . However, invalidation of the lysine demethylase LSD1 which catalyzes H3K4
and H3K9 demethylation, using specific inhibitors such as HCI-2509 or tranylcypromine, combined with
anti-PD-1 antibodies significantly decreased xenograph tumor growth and metastasis and increased the
number of TILs. Another study reported that contrary to breast cancer, 60% to 90% of pancreatic carcinoma
[58]
expressed PD-L1 . Interestingly, the authors showed in pancreatic cancer cell models that this expression